{"gene":"CHST11","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2002,"finding":"CHST11/C4ST-1 (chondroitin-4-sulfotransferase) was identified as a target gene induced by BMP2 signaling in a differentiation-dependent manner in mouse embryonic stem cells, establishing it as a downstream effector of BMP signaling.","method":"High-throughput gene trap screen in mouse ES cells; induction assessed in undifferentiated vs. differentiated (embryoid body) cells treated with BMP2, activin, and nodal","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene trap loss-of-function screen with differentiation-dependent BMP2 induction, single lab, functional genomic approach","pmids":["12351172"],"is_preprint":false},{"year":2004,"finding":"CHST11 is a Golgi-associated sulfotransferase belonging to the HNK1 family; a t(12;14)(q23;q32) translocation in B-CLL disrupts intron 2 of CHST11, generating IGH/CHST11 and CHST11/IGH fusion RNAs encoding truncated CHST11 proteins, deregulating a chondroitin-sulfate-dependent pathway in hematopoietic cells.","method":"FISH, Southern blot, Northern blot, 5'- and 3'-RACE on tumor RNA","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal molecular methods (FISH, Southern, Northern, RACE) in a single lab characterizing the translocation breakpoint and fusion transcripts","pmids":["15273723"],"is_preprint":false},{"year":2009,"finding":"Functional cis-regulatory modules in the C4ST-1/CHST11 locus were identified, including a functional promoter and TGFβ-responsive regulatory elements that can drive cell-type-specific gene expression; TGFβ positively regulates C4ST-1/CHST11 transcription through these modules.","method":"Bioinformatics conservation analysis; luciferase reporter assays in HEK293T and NmuMG cells with TGFβ treatment","journal":"Genetics and molecular research : GMR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter assays with TGFβ stimulation in two cell lines, single lab","pmids":["19937589"],"is_preprint":false},{"year":2011,"finding":"Genetic deficiency of Chst11/C4st1 in neural stem cells does NOT affect NSC proliferation, migration, or differentiation, whereas Chst14/D4st1 deficiency does; establishing that CS (via CHST11) and DS (via CHST14) have functionally distinct roles in neural progenitor biology.","method":"Loss-of-function using Chst11-deficient and Chst14-deficient mouse NSCs; proliferation, migration, and neurogenesis assays; receptor expression analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with defined cellular phenotype readouts, single lab, negative result for Chst11 on NSC biology","pmids":["22159417"],"is_preprint":false},{"year":2011,"finding":"C4ST-1/CHST11 and ChGn-2 are the specific Golgi enzymes whose elevated mRNA expression correlates with chondroitin sulfate chain elongation in atherosclerotic lesions, with their expression increasing as atherosclerosis progresses in LDLr KO mice on a western diet.","method":"qRT-PCR for C4ST-1, C4ST-2, ChGn-1, ChGn-2; gel filtration analysis of CS chain length; immunohistochemistry in LDLr KO mouse aortas at 2, 4, and 8 weeks of western diet","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — correlational in vivo expression data with functional CS chain length measurement, single lab, two orthogonal methods","pmids":["21284936"],"is_preprint":false},{"year":2012,"finding":"C4ST-1/CHST11 is a negatively regulated downstream target of oncogenic HRAS signaling; oncogenic HRAS represses C4ST-1 mRNA and protein expression and reduces chondroitin-4-sulfate levels; forced re-expression of C4ST-1 in Costello syndrome fibroblasts rescues proliferation and elastogenesis defects caused by oncogenic HRAS.","method":"Primary fibroblasts from Costello syndrome patients; oncogenic HRAS expression in normal fibroblasts; pharmacological interference with HRAS signaling; C4ST-1 forced expression rescue experiments; proliferation and elastogenesis assays","journal":"European journal of human genetics : EJHG","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss of HRAS and C4ST-1 experiments with defined cellular phenotypes, rescue experiments, patient fibroblasts corroborating the mechanism","pmids":["22317973"],"is_preprint":false},{"year":2013,"finding":"PPARγ directly regulates CHST11/C4ST1 transcription through two functional intronic PPARγ binding sites; CHST11 is upregulated during adipogenesis and its knockdown reduces intracellular lipid accumulation by lowering lipoprotein lipase (LPL) activity, likely because CHST11-mediated sulfation of chondroitin on the adipocyte surface is required for LPL binding.","method":"ChIP for PPARγ binding at intronic sites; siRNA knockdown of Chst11 in 3T3-L1 adipocytes; LPL activity assay; lipid accumulation assay; mRNA and protein expression during adipogenesis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP identifying direct PPARγ binding sites plus functional KD with defined LPL-activity phenotype, single lab, multiple orthogonal methods","pmids":["23696875"],"is_preprint":false},{"year":2014,"finding":"ARSB (arylsulfatase B) controls CHST11 mRNA expression in colonic epithelial cells: ARSB silencing leads to increased C4S sulfation, sequestration of BMP4 by C4S at the cell membrane, reduced BMP4 secretion, and consequently reduced CHST11 expression; exogenous BMP4 increases CHST11 expression through a phospho-Smad3 binding site in the CHST11 promoter; Wnt9A opposes this by reducing CHST11 expression.","method":"ARSB siRNA knockdown; BMP4 neutralizing antibody; recombinant BMP4 treatment; chromatin immunoprecipitation (ChIP) for pSmad3 at CHST11 promoter; Wnt9A siRNA; qRT-PCR in human colonic epithelial cells and ARSB-deficient mice","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA, antibody neutralization, recombinant protein, ChIP) identifying promoter-level mechanism, in vitro and in vivo corroboration","pmids":["25511584"],"is_preprint":false},{"year":2015,"finding":"Homozygous deletion encompassing part of CHST11 causes congenital limb malformation and is associated with malignant lymphoproliferative disease in human patients, establishing CHST11 as required for normal skeletal development and potentially as a tumor suppressor in the hematopoietic lineage.","method":"Whole-genome sequencing identifying homozygous 55 kb deletion in CHST11/MIR3922 locus; genotyping of family members; clinical characterization","journal":"Molecular genetics & genomic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic loss-of-function (homozygous deletion) with defined skeletal and hematopoietic phenotype, corroborated by mouse Chst11 KO data","pmids":["26436107"],"is_preprint":false},{"year":2016,"finding":"The OA-risk alleles of rs835487 and rs835488 (in intron 2 of CHST11) show differential enhancer activity in luciferase reporter assays; transcription factors SP1, SP3, YY1 and SUB1 bind more strongly to the risk-conferring alleles, as demonstrated by EMSA and supershift assays.","method":"Luciferase reporter assays; electrophoretic mobility shift assays (EMSA) and supershift assays with transcription factor antibodies; bioinformatics LD analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assay plus EMSA/supershift identifying specific TF-allele interactions, single lab, two orthogonal methods","pmids":["27391021"],"is_preprint":false},{"year":2016,"finding":"CHST11 knockdown in low-metastatic HCC cells increases invasive potential and drug resistance, while forced CHST11 expression in high-metastatic HCC cells reduces invasion and restores drug sensitivity; these effects operate via the MAPK signaling pathway, as MAPK activity was altered by CHST11 manipulation and pharmacological MAPK inhibition suppressed invasion.","method":"RNAi and forced expression in MHCC97L and MHCC97H cells; ECM invasion assay; drug sensitivity assay; in vivo antitumor activity assay; MAPK inhibitor (PD98059, SP600125) treatment; qRT-PCR and Western blotting","journal":"Digestive diseases and sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal KD and OE with defined phenotypes plus pharmacological epistasis placing CHST11 upstream of MAPK, single lab","pmids":["26993826"],"is_preprint":false},{"year":2018,"finding":"TGF-β1 increases CHST11 mRNA expression in vascular smooth muscle cells via Nox-dependent ROS production and Smad2 linker region phosphorylation; Nox inhibitors (DPI and apocynin) block TGF-β1-induced MAPK phosphorylation and CHST11 mRNA upregulation.","method":"Pharmacological inhibition of Nox (DPI, apocynin); Western blotting for Smad2 linker phosphorylation and MAPK; qRT-PCR for CHST11 mRNA; intracellular ROS fluorescence assay in VSMCs","journal":"Journal of cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with Nox inhibitors linking ROS/MAPK/Smad2 to CHST11 expression, multiple orthogonal methods, single lab","pmids":["30417274"],"is_preprint":false},{"year":2018,"finding":"A homozygous in-frame deletion of 15 nucleotides in CHST11 (c.467_481del; p.L156_N160del) removing five conserved amino acids causes an autosomal recessive syndrome with brachydactyly, overriding digits, clino-symphalangism, syndactyly, and skeletal defects in a consanguineous Pakistani family, confirming CHST11's essential role in skeletal morphogenesis.","method":"Homozygosity mapping using SNP array; exome sequencing; clinical characterization; in silico protein damage prediction","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics (homozygosity mapping + exome sequencing) identifying causal variant with defined skeletal phenotype, corroborated by mouse KO data","pmids":["29514872"],"is_preprint":false},{"year":2023,"finding":"KIAA1429/VIRMA-mediated m6A modification of CHST11 mRNA recruits YTHDF2 to reduce CHST11 mRNA stability and expression in DLBCL cells; reduced CHST11 expression decreases MOB1B expression, leading to inactivation of Hippo-YAP signaling.","method":"CRISPR/Cas9 KO and CRISPR/dCas9-VP64 activation of KIAA1429; RNA-seq; MeRIP-seq; RIP assays; luciferase activity assay; RNA stability experiments; co-immunoprecipitation; tumor xenograft models","journal":"Cellular & molecular biology letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (MeRIP-seq, RIP, RNA stability, Co-IP, CRISPR KO/activation, in vivo xenograft) establishing epistatic pathway from KIAA1429 → m6A-CHST11 → YTHDF2 → MOB1B → Hippo-YAP","pmids":["37076815"],"is_preprint":false},{"year":2023,"finding":"CHST11 overexpression in GBM promotes cell mobility; CHST11-mediated production of chondroitin 4-sulfate (C4S) on CSPG4 is required for CHST11-dependent cell invasiveness; treatment with a C4S-specific binding peptide (C4Sp) attenuates GBM cell invasiveness in vitro and improves survival in orthotopic glioma mouse models.","method":"Immunohistochemistry in glioma tissue; CHST11 KD/OE in GBM cell lines; in vitro invasion assay; C4Sp peptide treatment in vitro and in vivo orthotopic xenograft; RNA-seq dataset correlation for CSPG4-CHST11","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD/OE with defined invasiveness phenotype plus in vivo therapeutic rescue, single lab","pmids":["37559985"],"is_preprint":false},{"year":2025,"finding":"Overexpression of CHST11 in osteoblasts increases the chondroitin sulfate 4S/6S ratio and strongly suppresses osteoblast differentiation (reduced Akp2 expression and ALP activity); this inhibition operates through a Wnt3a/β-catenin/p53 axis, as C4ST-1 overexpression enhanced Wnt3a expression, upregulated p53, and pharmacological inhibition of β-catenin and p53 partially restored differentiation.","method":"C4ST-1 forced expression in osteoblasts; Akp2 gene expression and ALP activity assays; chondroitinase ABC treatment; pharmacological inhibition of β-catenin and p53; Wnt3a expression analysis","journal":"Biological & pharmaceutical bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with defined differentiation phenotype and pharmacological epistasis identifying Wnt/β-catenin-p53 pathway, single lab, multiple methods","pmids":["41656089"],"is_preprint":false},{"year":2025,"finding":"Hippocampal overexpression of Chst11 (increasing chondroitin-4-sulphation of CSPGs) impairs object recognition memory in rodents; treadmill exercise mitigates this memory impairment, linking CHST11-mediated CS sulfation to hippocampal memory performance.","method":"Viral vector-mediated hippocampal Chst11 overexpression; treadmill training; object recognition memory behavioral assay; gene expression analysis of aggrecan and perineuronal net composition","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic overexpression with defined behavioral phenotype and exercise rescue, but preprint, single lab","pmids":["bio_10.1101_2025.11.14.688432"],"is_preprint":true}],"current_model":"CHST11/C4ST-1 is a Golgi-resident chondroitin-4-O-sulfotransferase that transfers sulfate to position 4 of GalNAc residues on chondroitin chains; its expression is transcriptionally regulated by BMP2/BMP4 (via Smad3), TGFβ (via Nox/ROS/MAPK/Smad2 linker phosphorylation and intronic cis-regulatory modules), PPARγ (via direct intronic binding sites), and oncogenic HRAS (negative regulation), while post-transcriptionally it is repressed by KIAA1429-mediated m6A methylation and YTHDF2 recruitment; downstream, CHST11-dependent C4S production modulates LPL cell-surface binding in adipocytes, CSPG4-mediated GBM invasiveness, osteoblast differentiation via a Wnt/β-catenin-p53 axis, hippocampal CSPG composition affecting memory, and MOB1B/Hippo-YAP signaling in lymphoma, while loss-of-function in humans and mice causes severe skeletal malformations."},"narrative":{"mechanistic_narrative":"CHST11 (C4ST-1) is a Golgi-resident chondroitin-4-O-sulfotransferase of the HNK1 sulfotransferase family that catalyzes 4-O-sulfation of GalNAc residues on chondroitin chains, thereby setting the sulfation pattern of chondroitin sulfate proteoglycans across skeletal, vascular, adipose, neural, and tumor tissues [PMID:15273723, PMID:21284936]. Its transcription is a convergence point for developmental signaling: BMP2/BMP4 induce CHST11 through a phospho-Smad3 promoter element, and ARSB-controlled C4S sulfation feeds back on BMP4 availability to govern this loop, while Wnt9A opposes induction [PMID:12351172, PMID:25511584]; TGFβ likewise upregulates CHST11 through conserved cis-regulatory modules and, in vascular smooth muscle, via a Nox/ROS/MAPK/Smad2-linker phosphorylation cascade [PMID:19937589, PMID:30417274]; PPARγ directly binds two intronic sites to drive CHST11 during adipogenesis [PMID:23696875]; and oncogenic HRAS represses CHST11 and C4S, with re-expression rescuing the proliferation and elastogenesis defects of Costello syndrome fibroblasts [PMID:22317973]. Through its C4S product CHST11 acts on diverse downstream effectors: it is required for lipoprotein-lipase binding and lipid accumulation in adipocytes [PMID:23696875], for CSPG4-dependent glioblastoma invasion (blockable by a C4S-binding peptide) [PMID:37559985], and for suppression of osteoblast differentiation via a Wnt3a/β-catenin/p53 axis [PMID:41656089]. CHST11 expression is post-transcriptionally restrained by KIAA1429/VIRMA-mediated m6A methylation that recruits YTHDF2 to destabilize its mRNA, and in DLBCL this loss couples to reduced MOB1B and inactivation of Hippo-YAP signaling [PMID:37076815]. Loss-of-function in humans—through homozygous deletion or an in-frame deletion of five conserved residues—causes severe skeletal malformation syndromes, establishing CHST11 as essential for skeletal morphogenesis [PMID:26436107, PMID:29514872].","teleology":[{"year":2002,"claim":"Established CHST11 as a developmentally regulated effector by showing it is induced downstream of BMP2 in a differentiation-dependent manner, placing a sulfotransferase within morphogen signaling.","evidence":"Gene trap screen in mouse ES cells with BMP2/activin/nodal treatment across differentiation states","pmids":["12351172"],"confidence":"Medium","gaps":["Did not define the promoter elements mediating BMP2 induction","No enzymatic or sulfation-pattern readout linked to the induction"]},{"year":2004,"claim":"Identified CHST11 as a Golgi HNK1-family sulfotransferase and implicated it in hematopoietic malignancy via a translocation disrupting intron 2 and producing truncated IGH/CHST11 fusion transcripts.","evidence":"FISH, Southern/Northern blot, and 5'/3'-RACE on B-CLL tumor RNA","pmids":["15273723"],"confidence":"Medium","gaps":["Functional consequence of the truncated protein not tested enzymatically","Causality between fusion and transformation not established"]},{"year":2009,"claim":"Mapped functional cis-regulatory modules and showed TGFβ positively regulates CHST11 transcription, defining a second morphogen input to the locus.","evidence":"Conservation analysis and luciferase reporter assays in HEK293T and NmuMG cells with TGFβ","pmids":["19937589"],"confidence":"Medium","gaps":["Transcription factors binding the modules not identified here","Endogenous-locus relevance beyond reporters not shown"]},{"year":2011,"claim":"Distinguished CHST11's biological role from the related dermatan enzyme CHST14 by showing CHST11 loss does not impair neural stem cell behavior, indicating tissue-specific dispensability.","evidence":"Chst11- vs Chst14-deficient mouse NSC proliferation, migration, and neurogenesis assays","pmids":["22159417"],"confidence":"Medium","gaps":["Negative result does not exclude roles in other neural contexts","No measurement of residual CS sulfation in KO NSCs"]},{"year":2011,"claim":"Linked CHST11 expression to chondroitin sulfate chain elongation in disease by correlating its upregulation with progressive atherosclerotic remodeling.","evidence":"qRT-PCR and CS chain-length gel filtration plus IHC in LDLr KO mouse aortas over a western diet time course","pmids":["21284936"],"confidence":"Medium","gaps":["Correlative; no causal CHST11 manipulation in lesions","Cell type driving the expression change not resolved"]},{"year":2012,"claim":"Defined CHST11 as a target negatively regulated by oncogenic HRAS and demonstrated its functional importance by rescuing Costello syndrome fibroblast phenotypes.","evidence":"Reciprocal HRAS gain/loss, pharmacological HRAS inhibition, and C4ST-1 re-expression rescue in patient fibroblasts with proliferation/elastogenesis assays","pmids":["22317973"],"confidence":"High","gaps":["Transcriptional mechanism of HRAS repression not pinpointed","Sulfation substrate mediating elastogenesis rescue not identified"]},{"year":2013,"claim":"Established direct PPARγ transcriptional control of CHST11 and a downstream metabolic role in adipocyte lipid handling via LPL binding.","evidence":"PPARγ ChIP at intronic sites, Chst11 siRNA in 3T3-L1 adipocytes, LPL activity and lipid accumulation assays","pmids":["23696875"],"confidence":"Medium","gaps":["Direct requirement of C4S sulfation for LPL binding inferred, not biochemically proven","In vivo adipose relevance not tested"]},{"year":2014,"claim":"Resolved a feedback loop in which ARSB and BMP4 control CHST11 at the promoter through phospho-Smad3, with Wnt9A as an opposing input.","evidence":"ARSB siRNA, BMP4 neutralization/recombinant BMP4, pSmad3 ChIP at the CHST11 promoter, Wnt9A siRNA in colonic epithelium and ARSB-deficient mice","pmids":["25511584"],"confidence":"High","gaps":["Mechanism of Wnt9A repression not defined","Generality of the ARSB-BMP4 loop outside colonic epithelium unknown"]},{"year":2016,"claim":"Connected CHST11 intronic OA-risk variants to differential enhancer activity and allele-specific transcription factor binding.","evidence":"Luciferase reporters plus EMSA/supershift for SP1, SP3, YY1, SUB1 at risk alleles rs835487/rs835488","pmids":["27391021"],"confidence":"Medium","gaps":["Effect on endogenous CHST11 levels in cartilage not measured","Link to osteoarthritis pathology not functionally demonstrated"]},{"year":2016,"claim":"Positioned CHST11 as a suppressor of hepatocellular carcinoma invasion and drug resistance acting upstream of MAPK signaling.","evidence":"Reciprocal KD/OE in MHCC97L/H cells, invasion and drug-sensitivity assays, MAPK inhibitor epistasis, in vivo antitumor assay","pmids":["26993826"],"confidence":"Medium","gaps":["CS substrate mediating MAPK modulation not identified","Direction of regulation differs from invasion-promoting role elsewhere"]},{"year":2018,"claim":"Detailed the TGFβ1 signaling route to CHST11 in vascular smooth muscle through Nox/ROS, MAPK, and Smad2 linker phosphorylation.","evidence":"Nox inhibition (DPI, apocynin), Western blots for Smad2 linker/MAPK, ROS assay, and CHST11 qRT-PCR in VSMCs","pmids":["30417274"],"confidence":"Medium","gaps":["Promoter elements receiving this signal not mapped","Downstream CS/vascular consequence not measured"]},{"year":2018,"claim":"Confirmed CHST11's essential role in skeletal morphogenesis through an autosomal recessive in-frame deletion removing five conserved residues.","evidence":"Homozygosity mapping and exome sequencing in a consanguineous family with brachydactyly/syndactyly syndrome","pmids":["29514872"],"confidence":"Medium","gaps":["Enzymatic effect of the deletion not biochemically assayed","Mechanistic link from sulfation loss to digit patterning not defined"]},{"year":2023,"claim":"Established post-transcriptional control of CHST11 by m6A methylation and its coupling to oncogenic signaling in lymphoma.","evidence":"KIAA1429 CRISPR KO/dCas9 activation, MeRIP-seq, RIP, RNA-stability and Co-IP assays, and xenografts tracing KIAA1429→m6A-CHST11→YTHDF2→MOB1B→Hippo-YAP","pmids":["37076815"],"confidence":"High","gaps":["How reduced CHST11 lowers MOB1B mechanistically not resolved","Whether the effect requires CHST11 enzymatic activity untested"]},{"year":2023,"claim":"Demonstrated that CHST11-generated C4S on CSPG4 drives glioblastoma invasion and is therapeutically targetable.","evidence":"CHST11 KD/OE in GBM lines, invasion assays, C4S-binding peptide treatment in vitro and in orthotopic xenografts","pmids":["37559985"],"confidence":"Medium","gaps":["Direct sulfation of CSPG4 by CHST11 inferred from correlation/function","Signaling pathway downstream of C4S-CSPG4 not delineated"]},{"year":2025,"claim":"Identified CHST11 as a suppressor of osteoblast differentiation acting through altered 4S/6S ratio and a Wnt3a/β-catenin/p53 axis.","evidence":"C4ST-1 overexpression in osteoblasts with ALP/Akp2 readouts, chondroitinase ABC, and β-catenin/p53 pharmacological inhibition","pmids":["41656089"],"confidence":"Medium","gaps":["How sulfation ratio activates Wnt3a not mechanistically defined","In vivo bone phenotype of overexpression not tested"]},{"year":2025,"claim":"Extended CHST11's CS-sulfation role to brain function by linking hippocampal overexpression to impaired recognition memory rescuable by exercise.","evidence":"Viral hippocampal Chst11 overexpression, object recognition assay, exercise intervention, perineuronal net/aggrecan analysis (preprint)","pmids":["bio_10.1101_2025.11.14.688432"],"confidence":"Medium","gaps":["Preprint, single lab, not peer-reviewed","Mechanism connecting CS sulfation to memory circuits not resolved"]},{"year":null,"claim":"It remains unresolved how CHST11's single enzymatic output—C4S sulfation—produces opposing context-dependent outcomes (tumor-suppressive in HCC, invasion-promoting in GBM; differentiation-suppressing in osteoblasts) and which substrate proteoglycans mediate each phenotype.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified substrate-specificity map across tissues","Enzymatic activity not directly tied to most disease phenotypes","No structural model of the human enzyme in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,4,6,14,15]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,4]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7,11,13,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,8,12,15]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NPF2","full_name":"Carbohydrate sulfotransferase 11","aliases":["Chondroitin 4-O-sulfotransferase 1","Chondroitin 4-sulfotransferase 1","C4S-1","C4ST-1","C4ST1"],"length_aa":352,"mass_kda":41.6,"function":"Catalyzes the transfer of sulfate to position 4 of the N-acetylgalactosamine (GalNAc) residue of chondroitin. Chondroitin sulfate constitutes the predominant proteoglycan present in cartilage and is distributed on the surfaces of many cells and extracellular matrices. Can also sulfate Gal residues in desulfated dermatan sulfate. Preferentially sulfates in GlcA->GalNAc unit than in IdoA->GalNAc unit. Does not form 4, 6-di-O-sulfated GalNAc when chondroitin sulfate C is used as an acceptor","subcellular_location":"Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q9NPF2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHST11","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CHST11","total_profiled":1310},"omim":[{"mim_id":"618167","title":"OSTEOCHONDRODYSPLASIA, BRACHYDACTYLY, AND OVERLAPPING MALFORMED DIGITS; OCBMD","url":"https://www.omim.org/entry/618167"},{"mim_id":"612073","title":"MITOCHONDRIAL DNA DEPLETION SYNDROME 5 (ENCEPHALOMYOPATHIC WITH OR WITHOUT METHYLMALONIC ACIDURIA); MTDPS5","url":"https://www.omim.org/entry/612073"},{"mim_id":"610128","title":"CARBOHYDRATE SULFOTRANSFERASE 11; CHST11","url":"https://www.omim.org/entry/610128"},{"mim_id":"610124","title":"CARBOHYDRATE SULFOTRANSFERASE 13; CHST13","url":"https://www.omim.org/entry/610124"},{"mim_id":"603921","title":"SUCCINATE-CoA LIGASE, ADP-FORMING, SUBUNIT BETA; SUCLA2","url":"https://www.omim.org/entry/603921"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":36.7},{"tissue":"choroid plexus","ntpm":32.8}],"url":"https://www.proteinatlas.org/search/CHST11"},"hgnc":{"alias_symbol":["C4ST1","C4St-1","C4ST","HSA269537"],"prev_symbol":[]},"alphafold":{"accession":"Q9NPF2","domains":[{"cath_id":"-","chopping":"58-187_260-307","consensus_level":"medium","plddt":92.4776,"start":58,"end":307},{"cath_id":"-","chopping":"189-257_310-336","consensus_level":"medium","plddt":95.9331,"start":189,"end":336}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPF2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPF2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPF2-F1-predicted_aligned_error_v6.png","plddt_mean":89.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHST11","jax_strain_url":"https://www.jax.org/strain/search?query=CHST11"},"sequence":{"accession":"Q9NPF2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NPF2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NPF2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPF2"}},"corpus_meta":[{"pmid":"37076815","id":"PMC_37076815","title":"KIAA1429-mediated m6A modification of CHST11 promotes progression of diffuse large B-cell lymphoma by regulating Hippo-YAP pathway.","date":"2023","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/37076815","citation_count":37,"is_preprint":false},{"pmid":"30417274","id":"PMC_30417274","title":"Transforming growth factor-β1 mediated CHST11 and CHSY1 mRNA expression is ROS dependent in vascular smooth muscle cells.","date":"2018","source":"Journal of cell communication and signaling","url":"https://pubmed.ncbi.nlm.nih.gov/30417274","citation_count":36,"is_preprint":false},{"pmid":"21284936","id":"PMC_21284936","title":"Correlation of C4ST-1 and ChGn-2 expression with chondroitin sulfate chain elongation in atherosclerosis.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21284936","citation_count":34,"is_preprint":false},{"pmid":"22159417","id":"PMC_22159417","title":"Dermatan sulfotransferase Chst14/D4st1, but not chondroitin sulfotransferase Chst11/C4st1, regulates proliferation and neurogenesis of neural progenitor cells.","date":"2011","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22159417","citation_count":33,"is_preprint":false},{"pmid":"12351172","id":"PMC_12351172","title":"A high-throughput induction gene trap approach defines C4ST as a target of BMP signaling.","date":"2002","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/12351172","citation_count":28,"is_preprint":false},{"pmid":"29514872","id":"PMC_29514872","title":"Homozygous CHST11 mutation in chondrodysplasia, brachydactyly, overriding digits, clino-symphalangism and synpolydactyly.","date":"2018","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29514872","citation_count":22,"is_preprint":false},{"pmid":"25511584","id":"PMC_25511584","title":"Regulation of chondroitin-4-sulfotransferase (CHST11) expression by opposing effects of arylsulfatase B on BMP4 and Wnt9A.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25511584","citation_count":17,"is_preprint":false},{"pmid":"22317973","id":"PMC_22317973","title":"C4ST-1/CHST11-controlled chondroitin sulfation interferes with oncogenic HRAS signaling in Costello syndrome.","date":"2012","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/22317973","citation_count":16,"is_preprint":false},{"pmid":"15273723","id":"PMC_15273723","title":"Deregulation of the carbohydrate (chondroitin 4) sulfotransferase 11 (CHST11) gene in a B-cell chronic lymphocytic leukemia with a t(12;14)(q23;q32).","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15273723","citation_count":16,"is_preprint":false},{"pmid":"26993826","id":"PMC_26993826","title":"CHST11/13 Regulate the Metastasis and Chemosensitivity of Human Hepatocellular Carcinoma Cells Via Mitogen-Activated Protein Kinase Pathway.","date":"2016","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26993826","citation_count":15,"is_preprint":false},{"pmid":"19937589","id":"PMC_19937589","title":"Identification and characterization of TGFbeta-dependent and -independent cis-regulatory modules in the C4ST-1/CHST11 locus.","date":"2009","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/19937589","citation_count":13,"is_preprint":false},{"pmid":"23696875","id":"PMC_23696875","title":"PPARγ regulates expression of carbohydrate sulfotransferase 11 (CHST11/C4ST1), a regulator of LPL cell surface binding.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23696875","citation_count":11,"is_preprint":false},{"pmid":"26436107","id":"PMC_26436107","title":"Inherited CHST11/MIR3922 deletion is associated with a novel recessive syndrome presenting with skeletal malformation and malignant lymphoproliferative disease.","date":"2015","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26436107","citation_count":11,"is_preprint":false},{"pmid":"36181245","id":"PMC_36181245","title":"The CHST11 gene is linked to lung cancer and pulmonary fibrosis.","date":"2022","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36181245","citation_count":9,"is_preprint":false},{"pmid":"27391021","id":"PMC_27391021","title":"Functional Characterization of the Osteoarthritis Susceptibility Mapping to CHST11-A Bioinformatics and Molecular Study.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27391021","citation_count":7,"is_preprint":false},{"pmid":"40409655","id":"PMC_40409655","title":"Chondroitin sulfate reverses tibial dyschondroplasia, broiler chondrocyte proliferation and differentiation dysfunction via the CHST11/β-Catenin pathway.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40409655","citation_count":4,"is_preprint":false},{"pmid":"38565604","id":"PMC_38565604","title":"Effect of CHST11, a novel biomarker, on the biological functionalities of clear cell renal cell carcinoma.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38565604","citation_count":4,"is_preprint":false},{"pmid":"32302771","id":"PMC_32302771","title":"Cloning and characterization of chst11 from Procambarus clarkii involved in the host immune response of white spot syndrome virus and Aeromonas hydrophila.","date":"2020","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32302771","citation_count":4,"is_preprint":false},{"pmid":"37559985","id":"PMC_37559985","title":"CHST11-modified chondroitin 4-sulfate as a potential therapeutic target for glioblastoma.","date":"2023","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/37559985","citation_count":2,"is_preprint":false},{"pmid":"41656089","id":"PMC_41656089","title":"C4ST-1 Overexpression Suppresses Osteoblast Differentiation via a Wnt/β-Catenin-p53 Axis.","date":"2026","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/41656089","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.14.688432","title":"Exercise remodels hippocampal extracellular matrix to alleviate chondroitin-4-sulphate–induced memory impairment","date":"2025-11-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.14.688432","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13690,"output_tokens":4856,"usd":0.056955,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12957,"output_tokens":4930,"usd":0.094018,"stage2_stop_reason":"end_turn"},"total_usd":0.150973,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"CHST11/C4ST-1 (chondroitin-4-sulfotransferase) was identified as a target gene induced by BMP2 signaling in a differentiation-dependent manner in mouse embryonic stem cells, establishing it as a downstream effector of BMP signaling.\",\n      \"method\": \"High-throughput gene trap screen in mouse ES cells; induction assessed in undifferentiated vs. differentiated (embryoid body) cells treated with BMP2, activin, and nodal\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene trap loss-of-function screen with differentiation-dependent BMP2 induction, single lab, functional genomic approach\",\n      \"pmids\": [\"12351172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CHST11 is a Golgi-associated sulfotransferase belonging to the HNK1 family; a t(12;14)(q23;q32) translocation in B-CLL disrupts intron 2 of CHST11, generating IGH/CHST11 and CHST11/IGH fusion RNAs encoding truncated CHST11 proteins, deregulating a chondroitin-sulfate-dependent pathway in hematopoietic cells.\",\n      \"method\": \"FISH, Southern blot, Northern blot, 5'- and 3'-RACE on tumor RNA\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal molecular methods (FISH, Southern, Northern, RACE) in a single lab characterizing the translocation breakpoint and fusion transcripts\",\n      \"pmids\": [\"15273723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Functional cis-regulatory modules in the C4ST-1/CHST11 locus were identified, including a functional promoter and TGFβ-responsive regulatory elements that can drive cell-type-specific gene expression; TGFβ positively regulates C4ST-1/CHST11 transcription through these modules.\",\n      \"method\": \"Bioinformatics conservation analysis; luciferase reporter assays in HEK293T and NmuMG cells with TGFβ treatment\",\n      \"journal\": \"Genetics and molecular research : GMR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter assays with TGFβ stimulation in two cell lines, single lab\",\n      \"pmids\": [\"19937589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Genetic deficiency of Chst11/C4st1 in neural stem cells does NOT affect NSC proliferation, migration, or differentiation, whereas Chst14/D4st1 deficiency does; establishing that CS (via CHST11) and DS (via CHST14) have functionally distinct roles in neural progenitor biology.\",\n      \"method\": \"Loss-of-function using Chst11-deficient and Chst14-deficient mouse NSCs; proliferation, migration, and neurogenesis assays; receptor expression analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with defined cellular phenotype readouts, single lab, negative result for Chst11 on NSC biology\",\n      \"pmids\": [\"22159417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"C4ST-1/CHST11 and ChGn-2 are the specific Golgi enzymes whose elevated mRNA expression correlates with chondroitin sulfate chain elongation in atherosclerotic lesions, with their expression increasing as atherosclerosis progresses in LDLr KO mice on a western diet.\",\n      \"method\": \"qRT-PCR for C4ST-1, C4ST-2, ChGn-1, ChGn-2; gel filtration analysis of CS chain length; immunohistochemistry in LDLr KO mouse aortas at 2, 4, and 8 weeks of western diet\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — correlational in vivo expression data with functional CS chain length measurement, single lab, two orthogonal methods\",\n      \"pmids\": [\"21284936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"C4ST-1/CHST11 is a negatively regulated downstream target of oncogenic HRAS signaling; oncogenic HRAS represses C4ST-1 mRNA and protein expression and reduces chondroitin-4-sulfate levels; forced re-expression of C4ST-1 in Costello syndrome fibroblasts rescues proliferation and elastogenesis defects caused by oncogenic HRAS.\",\n      \"method\": \"Primary fibroblasts from Costello syndrome patients; oncogenic HRAS expression in normal fibroblasts; pharmacological interference with HRAS signaling; C4ST-1 forced expression rescue experiments; proliferation and elastogenesis assays\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss of HRAS and C4ST-1 experiments with defined cellular phenotypes, rescue experiments, patient fibroblasts corroborating the mechanism\",\n      \"pmids\": [\"22317973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PPARγ directly regulates CHST11/C4ST1 transcription through two functional intronic PPARγ binding sites; CHST11 is upregulated during adipogenesis and its knockdown reduces intracellular lipid accumulation by lowering lipoprotein lipase (LPL) activity, likely because CHST11-mediated sulfation of chondroitin on the adipocyte surface is required for LPL binding.\",\n      \"method\": \"ChIP for PPARγ binding at intronic sites; siRNA knockdown of Chst11 in 3T3-L1 adipocytes; LPL activity assay; lipid accumulation assay; mRNA and protein expression during adipogenesis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP identifying direct PPARγ binding sites plus functional KD with defined LPL-activity phenotype, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23696875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ARSB (arylsulfatase B) controls CHST11 mRNA expression in colonic epithelial cells: ARSB silencing leads to increased C4S sulfation, sequestration of BMP4 by C4S at the cell membrane, reduced BMP4 secretion, and consequently reduced CHST11 expression; exogenous BMP4 increases CHST11 expression through a phospho-Smad3 binding site in the CHST11 promoter; Wnt9A opposes this by reducing CHST11 expression.\",\n      \"method\": \"ARSB siRNA knockdown; BMP4 neutralizing antibody; recombinant BMP4 treatment; chromatin immunoprecipitation (ChIP) for pSmad3 at CHST11 promoter; Wnt9A siRNA; qRT-PCR in human colonic epithelial cells and ARSB-deficient mice\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA, antibody neutralization, recombinant protein, ChIP) identifying promoter-level mechanism, in vitro and in vivo corroboration\",\n      \"pmids\": [\"25511584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Homozygous deletion encompassing part of CHST11 causes congenital limb malformation and is associated with malignant lymphoproliferative disease in human patients, establishing CHST11 as required for normal skeletal development and potentially as a tumor suppressor in the hematopoietic lineage.\",\n      \"method\": \"Whole-genome sequencing identifying homozygous 55 kb deletion in CHST11/MIR3922 locus; genotyping of family members; clinical characterization\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic loss-of-function (homozygous deletion) with defined skeletal and hematopoietic phenotype, corroborated by mouse Chst11 KO data\",\n      \"pmids\": [\"26436107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The OA-risk alleles of rs835487 and rs835488 (in intron 2 of CHST11) show differential enhancer activity in luciferase reporter assays; transcription factors SP1, SP3, YY1 and SUB1 bind more strongly to the risk-conferring alleles, as demonstrated by EMSA and supershift assays.\",\n      \"method\": \"Luciferase reporter assays; electrophoretic mobility shift assays (EMSA) and supershift assays with transcription factor antibodies; bioinformatics LD analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assay plus EMSA/supershift identifying specific TF-allele interactions, single lab, two orthogonal methods\",\n      \"pmids\": [\"27391021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CHST11 knockdown in low-metastatic HCC cells increases invasive potential and drug resistance, while forced CHST11 expression in high-metastatic HCC cells reduces invasion and restores drug sensitivity; these effects operate via the MAPK signaling pathway, as MAPK activity was altered by CHST11 manipulation and pharmacological MAPK inhibition suppressed invasion.\",\n      \"method\": \"RNAi and forced expression in MHCC97L and MHCC97H cells; ECM invasion assay; drug sensitivity assay; in vivo antitumor activity assay; MAPK inhibitor (PD98059, SP600125) treatment; qRT-PCR and Western blotting\",\n      \"journal\": \"Digestive diseases and sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal KD and OE with defined phenotypes plus pharmacological epistasis placing CHST11 upstream of MAPK, single lab\",\n      \"pmids\": [\"26993826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TGF-β1 increases CHST11 mRNA expression in vascular smooth muscle cells via Nox-dependent ROS production and Smad2 linker region phosphorylation; Nox inhibitors (DPI and apocynin) block TGF-β1-induced MAPK phosphorylation and CHST11 mRNA upregulation.\",\n      \"method\": \"Pharmacological inhibition of Nox (DPI, apocynin); Western blotting for Smad2 linker phosphorylation and MAPK; qRT-PCR for CHST11 mRNA; intracellular ROS fluorescence assay in VSMCs\",\n      \"journal\": \"Journal of cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with Nox inhibitors linking ROS/MAPK/Smad2 to CHST11 expression, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"30417274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A homozygous in-frame deletion of 15 nucleotides in CHST11 (c.467_481del; p.L156_N160del) removing five conserved amino acids causes an autosomal recessive syndrome with brachydactyly, overriding digits, clino-symphalangism, syndactyly, and skeletal defects in a consanguineous Pakistani family, confirming CHST11's essential role in skeletal morphogenesis.\",\n      \"method\": \"Homozygosity mapping using SNP array; exome sequencing; clinical characterization; in silico protein damage prediction\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetics (homozygosity mapping + exome sequencing) identifying causal variant with defined skeletal phenotype, corroborated by mouse KO data\",\n      \"pmids\": [\"29514872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIAA1429/VIRMA-mediated m6A modification of CHST11 mRNA recruits YTHDF2 to reduce CHST11 mRNA stability and expression in DLBCL cells; reduced CHST11 expression decreases MOB1B expression, leading to inactivation of Hippo-YAP signaling.\",\n      \"method\": \"CRISPR/Cas9 KO and CRISPR/dCas9-VP64 activation of KIAA1429; RNA-seq; MeRIP-seq; RIP assays; luciferase activity assay; RNA stability experiments; co-immunoprecipitation; tumor xenograft models\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (MeRIP-seq, RIP, RNA stability, Co-IP, CRISPR KO/activation, in vivo xenograft) establishing epistatic pathway from KIAA1429 → m6A-CHST11 → YTHDF2 → MOB1B → Hippo-YAP\",\n      \"pmids\": [\"37076815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CHST11 overexpression in GBM promotes cell mobility; CHST11-mediated production of chondroitin 4-sulfate (C4S) on CSPG4 is required for CHST11-dependent cell invasiveness; treatment with a C4S-specific binding peptide (C4Sp) attenuates GBM cell invasiveness in vitro and improves survival in orthotopic glioma mouse models.\",\n      \"method\": \"Immunohistochemistry in glioma tissue; CHST11 KD/OE in GBM cell lines; in vitro invasion assay; C4Sp peptide treatment in vitro and in vivo orthotopic xenograft; RNA-seq dataset correlation for CSPG4-CHST11\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD/OE with defined invasiveness phenotype plus in vivo therapeutic rescue, single lab\",\n      \"pmids\": [\"37559985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Overexpression of CHST11 in osteoblasts increases the chondroitin sulfate 4S/6S ratio and strongly suppresses osteoblast differentiation (reduced Akp2 expression and ALP activity); this inhibition operates through a Wnt3a/β-catenin/p53 axis, as C4ST-1 overexpression enhanced Wnt3a expression, upregulated p53, and pharmacological inhibition of β-catenin and p53 partially restored differentiation.\",\n      \"method\": \"C4ST-1 forced expression in osteoblasts; Akp2 gene expression and ALP activity assays; chondroitinase ABC treatment; pharmacological inhibition of β-catenin and p53; Wnt3a expression analysis\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with defined differentiation phenotype and pharmacological epistasis identifying Wnt/β-catenin-p53 pathway, single lab, multiple methods\",\n      \"pmids\": [\"41656089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Hippocampal overexpression of Chst11 (increasing chondroitin-4-sulphation of CSPGs) impairs object recognition memory in rodents; treadmill exercise mitigates this memory impairment, linking CHST11-mediated CS sulfation to hippocampal memory performance.\",\n      \"method\": \"Viral vector-mediated hippocampal Chst11 overexpression; treadmill training; object recognition memory behavioral assay; gene expression analysis of aggrecan and perineuronal net composition\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic overexpression with defined behavioral phenotype and exercise rescue, but preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.11.14.688432\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CHST11/C4ST-1 is a Golgi-resident chondroitin-4-O-sulfotransferase that transfers sulfate to position 4 of GalNAc residues on chondroitin chains; its expression is transcriptionally regulated by BMP2/BMP4 (via Smad3), TGFβ (via Nox/ROS/MAPK/Smad2 linker phosphorylation and intronic cis-regulatory modules), PPARγ (via direct intronic binding sites), and oncogenic HRAS (negative regulation), while post-transcriptionally it is repressed by KIAA1429-mediated m6A methylation and YTHDF2 recruitment; downstream, CHST11-dependent C4S production modulates LPL cell-surface binding in adipocytes, CSPG4-mediated GBM invasiveness, osteoblast differentiation via a Wnt/β-catenin-p53 axis, hippocampal CSPG composition affecting memory, and MOB1B/Hippo-YAP signaling in lymphoma, while loss-of-function in humans and mice causes severe skeletal malformations.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHST11 (C4ST-1) is a Golgi-resident chondroitin-4-O-sulfotransferase of the HNK1 sulfotransferase family that catalyzes 4-O-sulfation of GalNAc residues on chondroitin chains, thereby setting the sulfation pattern of chondroitin sulfate proteoglycans across skeletal, vascular, adipose, neural, and tumor tissues [#1, #4]. Its transcription is a convergence point for developmental signaling: BMP2/BMP4 induce CHST11 through a phospho-Smad3 promoter element, and ARSB-controlled C4S sulfation feeds back on BMP4 availability to govern this loop, while Wnt9A opposes induction [#0, #7]; TGF\\u03b2 likewise upregulates CHST11 through conserved cis-regulatory modules and, in vascular smooth muscle, via a Nox/ROS/MAPK/Smad2-linker phosphorylation cascade [#2, #11]; PPAR\\u03b3 directly binds two intronic sites to drive CHST11 during adipogenesis [#6]; and oncogenic HRAS represses CHST11 and C4S, with re-expression rescuing the proliferation and elastogenesis defects of Costello syndrome fibroblasts [#5]. Through its C4S product CHST11 acts on diverse downstream effectors: it is required for lipoprotein-lipase binding and lipid accumulation in adipocytes [#6], for CSPG4-dependent glioblastoma invasion (blockable by a C4S-binding peptide) [#14], and for suppression of osteoblast differentiation via a Wnt3a/\\u03b2-catenin/p53 axis [#15]. CHST11 expression is post-transcriptionally restrained by KIAA1429/VIRMA-mediated m6A methylation that recruits YTHDF2 to destabilize its mRNA, and in DLBCL this loss couples to reduced MOB1B and inactivation of Hippo-YAP signaling [#13]. Loss-of-function in humans\\u2014through homozygous deletion or an in-frame deletion of five conserved residues\\u2014causes severe skeletal malformation syndromes, establishing CHST11 as essential for skeletal morphogenesis [#8, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established CHST11 as a developmentally regulated effector by showing it is induced downstream of BMP2 in a differentiation-dependent manner, placing a sulfotransferase within morphogen signaling.\",\n      \"evidence\": \"Gene trap screen in mouse ES cells with BMP2/activin/nodal treatment across differentiation states\",\n      \"pmids\": [\"12351172\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the promoter elements mediating BMP2 induction\", \"No enzymatic or sulfation-pattern readout linked to the induction\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified CHST11 as a Golgi HNK1-family sulfotransferase and implicated it in hematopoietic malignancy via a translocation disrupting intron 2 and producing truncated IGH/CHST11 fusion transcripts.\",\n      \"evidence\": \"FISH, Southern/Northern blot, and 5'/3'-RACE on B-CLL tumor RNA\",\n      \"pmids\": [\"15273723\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the truncated protein not tested enzymatically\", \"Causality between fusion and transformation not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapped functional cis-regulatory modules and showed TGF\\u03b2 positively regulates CHST11 transcription, defining a second morphogen input to the locus.\",\n      \"evidence\": \"Conservation analysis and luciferase reporter assays in HEK293T and NmuMG cells with TGF\\u03b2\",\n      \"pmids\": [\"19937589\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factors binding the modules not identified here\", \"Endogenous-locus relevance beyond reporters not shown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Distinguished CHST11's biological role from the related dermatan enzyme CHST14 by showing CHST11 loss does not impair neural stem cell behavior, indicating tissue-specific dispensability.\",\n      \"evidence\": \"Chst11- vs Chst14-deficient mouse NSC proliferation, migration, and neurogenesis assays\",\n      \"pmids\": [\"22159417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result does not exclude roles in other neural contexts\", \"No measurement of residual CS sulfation in KO NSCs\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked CHST11 expression to chondroitin sulfate chain elongation in disease by correlating its upregulation with progressive atherosclerotic remodeling.\",\n      \"evidence\": \"qRT-PCR and CS chain-length gel filtration plus IHC in LDLr KO mouse aortas over a western diet time course\",\n      \"pmids\": [\"21284936\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative; no causal CHST11 manipulation in lesions\", \"Cell type driving the expression change not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined CHST11 as a target negatively regulated by oncogenic HRAS and demonstrated its functional importance by rescuing Costello syndrome fibroblast phenotypes.\",\n      \"evidence\": \"Reciprocal HRAS gain/loss, pharmacological HRAS inhibition, and C4ST-1 re-expression rescue in patient fibroblasts with proliferation/elastogenesis assays\",\n      \"pmids\": [\"22317973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional mechanism of HRAS repression not pinpointed\", \"Sulfation substrate mediating elastogenesis rescue not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established direct PPAR\\u03b3 transcriptional control of CHST11 and a downstream metabolic role in adipocyte lipid handling via LPL binding.\",\n      \"evidence\": \"PPAR\\u03b3 ChIP at intronic sites, Chst11 siRNA in 3T3-L1 adipocytes, LPL activity and lipid accumulation assays\",\n      \"pmids\": [\"23696875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct requirement of C4S sulfation for LPL binding inferred, not biochemically proven\", \"In vivo adipose relevance not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved a feedback loop in which ARSB and BMP4 control CHST11 at the promoter through phospho-Smad3, with Wnt9A as an opposing input.\",\n      \"evidence\": \"ARSB siRNA, BMP4 neutralization/recombinant BMP4, pSmad3 ChIP at the CHST11 promoter, Wnt9A siRNA in colonic epithelium and ARSB-deficient mice\",\n      \"pmids\": [\"25511584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Wnt9A repression not defined\", \"Generality of the ARSB-BMP4 loop outside colonic epithelium unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected CHST11 intronic OA-risk variants to differential enhancer activity and allele-specific transcription factor binding.\",\n      \"evidence\": \"Luciferase reporters plus EMSA/supershift for SP1, SP3, YY1, SUB1 at risk alleles rs835487/rs835488\",\n      \"pmids\": [\"27391021\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect on endogenous CHST11 levels in cartilage not measured\", \"Link to osteoarthritis pathology not functionally demonstrated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Positioned CHST11 as a suppressor of hepatocellular carcinoma invasion and drug resistance acting upstream of MAPK signaling.\",\n      \"evidence\": \"Reciprocal KD/OE in MHCC97L/H cells, invasion and drug-sensitivity assays, MAPK inhibitor epistasis, in vivo antitumor assay\",\n      \"pmids\": [\"26993826\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CS substrate mediating MAPK modulation not identified\", \"Direction of regulation differs from invasion-promoting role elsewhere\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Detailed the TGF\\u03b21 signaling route to CHST11 in vascular smooth muscle through Nox/ROS, MAPK, and Smad2 linker phosphorylation.\",\n      \"evidence\": \"Nox inhibition (DPI, apocynin), Western blots for Smad2 linker/MAPK, ROS assay, and CHST11 qRT-PCR in VSMCs\",\n      \"pmids\": [\"30417274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Promoter elements receiving this signal not mapped\", \"Downstream CS/vascular consequence not measured\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Confirmed CHST11's essential role in skeletal morphogenesis through an autosomal recessive in-frame deletion removing five conserved residues.\",\n      \"evidence\": \"Homozygosity mapping and exome sequencing in a consanguineous family with brachydactyly/syndactyly syndrome\",\n      \"pmids\": [\"29514872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzymatic effect of the deletion not biochemically assayed\", \"Mechanistic link from sulfation loss to digit patterning not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established post-transcriptional control of CHST11 by m6A methylation and its coupling to oncogenic signaling in lymphoma.\",\n      \"evidence\": \"KIAA1429 CRISPR KO/dCas9 activation, MeRIP-seq, RIP, RNA-stability and Co-IP assays, and xenografts tracing KIAA1429\\u2192m6A-CHST11\\u2192YTHDF2\\u2192MOB1B\\u2192Hippo-YAP\",\n      \"pmids\": [\"37076815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How reduced CHST11 lowers MOB1B mechanistically not resolved\", \"Whether the effect requires CHST11 enzymatic activity untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that CHST11-generated C4S on CSPG4 drives glioblastoma invasion and is therapeutically targetable.\",\n      \"evidence\": \"CHST11 KD/OE in GBM lines, invasion assays, C4S-binding peptide treatment in vitro and in orthotopic xenografts\",\n      \"pmids\": [\"37559985\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct sulfation of CSPG4 by CHST11 inferred from correlation/function\", \"Signaling pathway downstream of C4S-CSPG4 not delineated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified CHST11 as a suppressor of osteoblast differentiation acting through altered 4S/6S ratio and a Wnt3a/\\u03b2-catenin/p53 axis.\",\n      \"evidence\": \"C4ST-1 overexpression in osteoblasts with ALP/Akp2 readouts, chondroitinase ABC, and \\u03b2-catenin/p53 pharmacological inhibition\",\n      \"pmids\": [\"41656089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How sulfation ratio activates Wnt3a not mechanistically defined\", \"In vivo bone phenotype of overexpression not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended CHST11's CS-sulfation role to brain function by linking hippocampal overexpression to impaired recognition memory rescuable by exercise.\",\n      \"evidence\": \"Viral hippocampal Chst11 overexpression, object recognition assay, exercise intervention, perineuronal net/aggrecan analysis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.14.688432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab, not peer-reviewed\", \"Mechanism connecting CS sulfation to memory circuits not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how CHST11's single enzymatic output\\u2014C4S sulfation\\u2014produces opposing context-dependent outcomes (tumor-suppressive in HCC, invasion-promoting in GBM; differentiation-suppressing in osteoblasts) and which substrate proteoglycans mediate each phenotype.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified substrate-specificity map across tissues\", \"Enzymatic activity not directly tied to most disease phenotypes\", \"No structural model of the human enzyme in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 4, 6, 14, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7, 11, 13, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 8, 12, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}