Affinage

ASXL2

Putative Polycomb group protein ASXL2 · UniProt Q76L83

Length
1435 aa
Mass
153.8 kDa
Annotated
2026-06-09
31 papers in source corpus 14 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ASXL2 is an epigenetic scaffold protein that couples histone-modifying machineries to chromatin to control gene expression programs governing hematopoiesis, bone remodeling, cardiac function, and metabolism (PMID:26416890, PMID:19270745, PMID:21490954). It forms a mutually exclusive complex with the deubiquitinase BAP1, engaging the BAP1 C-terminal domain through its ASXM domain to enable ubiquitin binding and H2A-K119 deubiquitination; BAP1 in turn stabilizes ASXL2 protein, and cancer-associated ASXL2 mutations disrupt BAP1 DUB activity, linking this axis to senescence control and tumor suppression (PMID:26416890). Within the BAP1 complex, ASXL2 bridges to the MLL3/COMPASS H3K4 methyltransferase to sustain enhancer occupancy and target-gene expression, an interaction blocked by CARM1/PRMT4-mediated methylation of ASXL2 at R639/R641 (PMID:36197977). ASXL2 also acts as a repressive cofactor, co-occupying target promoters with EZH2 to maintain H3K27me3-dependent silencing of genes such as cardiac β-MHC (PMID:19270745, PMID:23046516), while its PHD finger reads dimethylated H3K4 and recruits LSD1, UTX, and MLL2 to mediate ligand-dependent transcriptional activation by ERα and the nuclear receptors PPARγ and LXRα, integrating epigenetic control of lipid and glucose metabolism (PMID:26051940, PMID:26640146, PMID:24321552). Functionally, ASXL2 is required for normal hematopoietic stem cell self-renewal, and its loss causes MDS-like disease and promotes AML1-ETO-driven leukemogenesis through altered enhancer accessibility and histone marks (PMID:28516957, PMID:28593990), drives osteoclastogenesis and bone mineral density (PMID:26051940, PMID:21490954), and maintains adult ventricular function (PMID:19270745, PMID:23046516). Beyond these characterized roles, no further mechanistic detail has been established in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2009 High

    Establishing whether ASXL2 functions in chromatin regulation in vivo, this work showed it promotes Polycomb-associated H3K27me3 and governs body-axis patterning and heart development.

    Evidence Gene-trap Asxl2 knockout mice with H3K27me3 western blots, skeletal and cardiac phenotyping

    PMID:19270745

    Open questions at the time
    • Direct molecular partners mediating H3K27me3 changes not identified
    • Dual PcG/trxG activity not mechanistically resolved
  2. 2011 High

    Addressing the cellular basis of skeletal phenotypes, ASXL2 was shown to be cell-autonomously required for osteoclast formation and bone mineral density.

    Evidence Systems genetics (HMDP), Asxl2 knockout mice BMD phenotyping, siRNA knockdown in bone marrow macrophages with osteoclast differentiation assays

    PMID:21490954

    Open questions at the time
    • Molecular target genes in osteoclast lineage not defined
    • Chromatin mechanism in osteoclastogenesis unaddressed
  3. 2012 High

    To pinpoint how ASXL2 controls cardiac gene expression, this study showed it co-occupies the β-MHC promoter with EZH2 to maintain repression and ventricular function.

    Evidence Asxl2-/- echocardiography and ChIP for Asxl2/Ezh2 co-occupancy at the β-MHC promoter

    PMID:23046516

    Open questions at the time
    • Direct physical interaction between ASXL2 and EZH2 not demonstrated biochemically
    • Genome-wide co-occupancy not mapped
  4. 2013 Medium

    Testing whether ASXL family members differentially regulate nuclear receptors, ASXL2 was found to activate LXRα transcription in a ligand-dependent manner, opposite to ASXL1.

    Evidence Reporter assays, Co-IP, ChIP at ABCA1 promoter, siRNA knockdown with lipid accumulation readout

    PMID:24321552

    Open questions at the time
    • Single lab without independent replication
    • Histone-modifying machinery recruited to LXRα targets not defined
  5. 2014 Medium

    Identifying a negative regulator of ASXL2 cofactor activity, WTIP was shown to directly bind ASXL2 and repress its retinoic-acid-dependent transcriptional stimulation.

    Evidence Biochemical/genetic interaction assays and luciferase reporters in HeLa cells, epicardial co-expression

    PMID:25065743

    Open questions at the time
    • Single lab without independent replication
    • Physiological context of WTIP-ASXL2 regulation in vivo unresolved
  6. 2015 High

    Defining the core biochemical complex, ASXL2 was shown to form a BAP1-specific (mutually exclusive with ASXL1) complex via ASXM–CTD contact required for H2A-K119 deubiquitination, with BAP1 reciprocally stabilizing ASXL2 and cancer mutations disrupting DUB activity.

    Evidence Reciprocal Co-IP, in vitro DUB assays, BAP1 CTD/ASXM mutagenesis, senescence assays

    PMID:26416890

    Open questions at the time
    • Genome-wide deubiquitination targets not mapped
    • Structural basis of ASXM-CTD interaction not solved
  7. 2015 High

    Linking ASXL2 to nuclear-receptor and metabolic biology, it was shown to bind PPARγ and drive osteoclast differentiation and bone resorption through PPARγ/c-Fos and PGC-1β branches, with knockout mice osteopetrotic, lipodystrophic, and insulin resistant.

    Evidence Asxl2 knockout mice, osteoclast differentiation and bone resorption assays, signaling epistasis

    PMID:26051940

    Open questions at the time
    • Chromatin targets downstream of PPARγ/ASXL2 not defined
    • Direct PPARγ interaction interface not mapped
  8. 2015 High

    Establishing ASXL2 as an ERα coactivator scaffold, it was shown to bind ligand-bound ERα, read H3K4me2 via its PHD finger, and recruit LSD1/UTX/MLL2 to estrogen-responsive promoters to drive proliferation.

    Evidence Co-IP, ChIP-seq, PHD finger pulldowns, siRNA knockdown, xenograft assays

    PMID:26640146

    Open questions at the time
    • PHD reader specificity not structurally characterized
    • Interplay with the BAP1 complex at these loci unresolved
  9. 2017 High

    Two concurrent studies defined ASXL2's role in hematopoiesis, showing it is required for HSC self-renewal and that its loss causes MDS-like disease and promotes AML1-ETO leukemogenesis through altered enhancer accessibility and histone marks.

    Evidence Conditional Asxl2 knockout mice, HSC transplantation and paired-daughter assays, ATAC-seq, H3K27ac/H3K4me1/2 ChIP

    PMID:28516957 PMID:28593990

    Open questions at the time
    • Direct biochemical link between ASXL2 and RUNX1/AML1-ETO not established
    • Whether BAP1/MLL3 axis drives the hematopoietic phenotype unresolved
  10. 2020 High

    Probing cell-type-specific metabolic function, myeloid ASXL2 deletion was shown to protect against diet-induced obesity by preserving brown fat thermogenesis and catecholamine availability.

    Evidence LysM-Cre Asxl2 conditional KO, HFD metabolic phenotyping, in vivo nanoparticle siRNA, energy expenditure and catecholamine measurements

    PMID:32310225

    Open questions at the time
    • Chromatin targets in macrophages mediating the phenotype not identified
    • Connection to the BAP1/MLL3 complex untested
  11. 2022 High

    Resolving how the BAP1 complex couples deubiquitination to active marks, ASXL2 was shown to directly bridge BAP1 to MLL3/COMPASS, an interaction switched off by CARM1 methylation at R639/R641.

    Evidence Co-IP, ChIP-seq, siRNA, site-directed mutagenesis, arginine methylation assays

    PMID:36197977

    Open questions at the time
    • Structural basis of ASXL2-MLL3 contact unresolved
    • Physiological contexts where CARM1 regulates this switch not defined
  12. 2025 Medium

    Extending ASXL2's epigenetic balancing role to stem-cell differentiation, knockdown in periodontal ligament stem cells was shown to shift histone marks toward repression and impair osteogenesis.

    Evidence Lentiviral shRNA in hPDLSCs, ALP/Alizarin Red assays, histone modification western blots, qPCR

    PMID:40680514

    Open questions at the time
    • Single lab without independent replication
    • Direct gene targets and complex partners not defined
  13. 2026 Medium

    Connecting ASXL2 to ciliogenesis and male fertility, it was shown to maintain EZH2/H3K27me3-mediated repression of CEP162, the loss of which disrupts axonemal microtubule stability via TUBB3 competition.

    Evidence ASXL2 loss-of-function in spermatogenic cells, ChIP for EZH2/H3K27me3 at CEP162 promoter, protein competition assays, spermatid morphology

    PMID:41782374

    Open questions at the time
    • Single lab without independent replication
    • Direct ASXL2-EZH2 interaction not biochemically shown
    • In vivo fertility consequence not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ASXL2's two opposing activities — promoting H2A-K119 deubiquitination/H3K4 methylation versus sustaining EZH2-dependent H3K27me3 repression — are selected at a given locus and integrated with nuclear-receptor signaling remains unresolved.
  • No structural model of ASXL2 complexes
  • Rules governing activating-versus-repressive recruitment unknown
  • No human disease established by direct genetic evidence in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0140110 transcription regulator activity 2 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1430728 Metabolism 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
BAP1CARM1ESR1EZH2LXRAMLL3PPARGWTIP
Complex memberships
BAP1 complexMLL3/COMPASS

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 ASXL2 forms a mutually exclusive complex with BAP1 (distinct from the BAP1/ASXL1 complex); ASXL2 uses its ASXM domain to interact with the C-terminal domain (CTD) of BAP1, and this interaction is required for ubiquitin binding and H2A deubiquitination at Lys-119. BAP1 is essential for maintaining ASXL2 (but not ASXL1) protein stability, and cancer-associated loss of BAP1 results in ASXL2 destabilization. Co-immunoprecipitation, in vitro DUB activity assays, mutagenesis of BAP1 CTD and ASXM domains, cell proliferation and senescence assays The Journal of biological chemistry High 26416890
2015 Cancer-associated mutations in ASXL2 disrupt BAP1 DUB activity, and BAP1 interaction with ASXL2 regulates cell senescence, implicating the BAP1/ASXL2 axis in tumor suppression. Mutagenesis of ASXL2 cancer-associated variants, DUB activity assays, cell senescence assays The Journal of biological chemistry High 26416890
2022 ASXL2, as a subunit of the BAP1 complex, mediates a direct interaction with MLL3/COMPASS, and ASXL2 loss results in decreased MLL3 occupancy at enhancers and reduced BAP1-MLL3 target gene expression. PRMT4/CARM1 methylates ASXL2 at R639/R641, blocking its binding to MLL3 and impairing MLL3/COMPASS-dependent gene expression. Co-immunoprecipitation, ChIP-seq, siRNA knockdown, site-directed mutagenesis, arginine methylation assays Science advances High 36197977
2015 ASXL2 interacts with PPARγ and regulates osteoclast formation via a PPARγ/c-Fos-dependent pathway; ASXL2 is also required for RANK ligand- and thiazolidinedione-induced bone resorption independently of PGC-1β, and promotes osteoclast mitochondrial biogenesis in a PGC-1β-dependent but c-Fos-independent manner. ASXL2-/- mice are insulin resistant, lipodystrophic, and severely osteopetrotic due to failed osteoclast differentiation. Asxl2 knockout mice, osteoclast differentiation assays, bone resorption assays, signaling pathway epistasis experiments Cell reports High 26051940
2015 ASXL2 interacts with ligand-bound ERα and mediates ERα transcriptional activation. ASXL2 forms a complex with histone methylation modifiers LSD1, UTX, and MLL2, which are recruited to E2-responsive gene promoters via ASXL2, regulating methylations at H3K4, H3K9, and H3K27. The PHD finger of ASXL2 preferentially binds dimethylated H3K4, which is required for ERα activation. Co-immunoprecipitation, ChIP-seq, pulldown assays with PHD finger, siRNA knockdown, xenograft tumor assays Oncogene High 26640146
2009 Loss of Asxl2 in mice reduces trimethylation of histone H3 lysine 27 (H3K27me3) in the heart, demonstrating that Asxl2 promotes PcG-associated histone modification. Asxl2 mutant mice display both posterior and anterior transformations of the axial skeleton, indicating dual roles in PcG and trxG activity. Asxl2-/- mice develop enlarged hearts with impaired ventricular function. Gene-trap knockout mouse, histone modification analysis (western blot for H3K27me3), skeletal phenotyping, histological analysis PloS one High 19270745
2012 Asxl2 is required for maintenance of ventricular function and for repression of β-MHC in adult mouse hearts. Asxl2 and the histone methyltransferase Ezh2 co-localize to the β-MHC promoter, indicating Asxl2 directly represses β-MHC through Ezh2-mediated chromatin modification. Loss of Asxl2 causes progressive deterioration of ventricular function (~37% reduction in fractional shortening by 10 months). Asxl2-/- mice echocardiography, ChIP showing Asxl2 and Ezh2 co-occupancy at β-MHC promoter, cardiac gene expression analysis Journal of molecular and cellular cardiology High 23046516
2011 Asxl2 regulates bone mineral density and osteoclastogenesis; knockdown of Asxl2 in bone marrow macrophages impairs their ability to form osteoclasts. Asxl2 knockout mice have reduced BMD. GWAS/systems genetics in HMDP, Asxl2 knockout mice (BMD phenotyping), siRNA knockdown in bone marrow macrophages with osteoclast differentiation assays PLoS genetics High 21490954
2017 ASXL2 is required for normal haematopoietic stem cell self-renewal; Asxl2 loss promotes AML1-ETO-driven leukemogenesis. ASXL2 target genes strongly overlap with those of RUNX1 and AML1-ETO, and ASXL2 loss is associated with increased chromatin accessibility at putative enhancers of key leukemogenic loci. Asxl2 conditional knockout mice, hematopoietic stem cell transplantation assays, ATAC-seq for chromatin accessibility, gene expression analysis Nature communications High 28516957
2017 Deletion of Asxl2 in mice leads to MDS-like disease with expanded long-term HSCs and granulocyte-macrophage progenitors. Asxl2 loss enhances HSC self-renewal (paired daughter cell assays) and alters H3K27ac and H3K4me1/2 at loci critical for HSC self-renewal, differentiation, and apoptosis. Asxl2 knockout mice, bone marrow transplantation, paired daughter cell assays, histone modification ChIP analysis Nature communications High 28593990
2013 ASXL2 activates LXRα transcriptional activity through direct interaction with LXRα in the presence of ligand, while ASXL1 suppresses it; knockdown of ASXL2 decreases lipid accumulation in H4IIE cells. ChIP assays show ligand-dependent recruitment of ASXL2 to ABCA1 promoters. Transcriptional reporter assays, Co-immunoprecipitation, ChIP assay, siRNA knockdown with lipid accumulation readout Biochemical and biophysical research communications Medium 24321552
2014 ASXL2 directly interacts with the LIM domain-containing protein WTIP; WTIP represses ASXL2-stimulated retinoic acid-dependent transcription, blocking ASXL2's stimulatory effect. Both proteins are expressed in mouse embryonic epicardial cells. Genetic and biochemical interaction assays, luciferase reporter assays in HeLa cells, co-expression analysis in mouse embryonic epicardium Biochemical and biophysical research communications Medium 25065743
2020 Myeloid-specific deletion of Asxl2 confers resistance to diet-induced obesity by protecting energy expenditure and brown adipose tissue metabolism, associated with suppressed macrophage inflammatory cytokine expression and relatively increased catecholamines (due to suppressed catecholamine degradation by macrophages). Nanoparticle-based siRNA suppression of macrophage Asxl2 prevented HFD-induced obesity. Myeloid-specific Asxl2 conditional KO (LysM-Cre), high-fat diet metabolic phenotyping, nanoparticle siRNA delivery in vivo, energy expenditure measurements, cytokine/catecholamine measurements The Journal of clinical investigation High 32310225
2026 ASXL2 promotes EZH2 binding to the CEP162 promoter region (3482–3511 bp), maintaining H3K27me3 and repressing CEP162 transcription. Hypoxia-induced downregulation of ASXL2 reduces EZH2 occupancy, increases CEP162 expression, and CEP162 then competes with TUBA3A for TUBB3 binding, depleting ciliary TUBB3 and destabilizing axonemal microtubules, causing spermatid maturation defects. ASXL2 loss-of-function in spermatogenic cells, ChIP for EZH2/H3K27me3 at CEP162 promoter, protein binding/competition assays (TUBB3/CEP162/TUBA3A), spermatid morphology analysis Advanced science Medium 41782374
2025 ASXL2 knockdown in human periodontal ligament stem cells (hPDLSCs) impairs osteogenic differentiation, suppresses H3K4me3 (activating mark), and increases H2AK119ub and H3K27me3 (repressive marks) at osteogenic gene loci, demonstrating that ASXL2 modulates osteogenic competency through histone modification balance. Lentiviral shRNA knockdown in hPDLSCs, ALP activity assay, Alizarin Red mineralization, western blot for H3K4me3/H2AK119ub/H3K27me3, qPCR for osteogenic markers International dental journal Medium 40680514

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer. The Journal of biological chemistry 115 26416890
2011 Mouse genome-wide association and systems genetics identify Asxl2 as a regulator of bone mineral density and osteoclastogenesis. PLoS genetics 97 21490954
2014 Frequent ASXL2 mutations in acute myeloid leukemia patients with t(8;21)/RUNX1-RUNX1T1 chromosomal translocations. Blood 94 24973361
2003 Identification and characterization of ASXL2 gene in silico. International journal of oncology 90 12888926
2015 ASXL2 Regulates Glucose, Lipid, and Skeletal Homeostasis. Cell reports 63 26051940
2009 Functional conservation of Asxl2, a murine homolog for the Drosophila enhancer of trithorax and polycomb group gene Asx. PloS one 60 19270745
2017 ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia. Nature communications 58 28516957
2015 Functional proteomics of the epigenetic regulators ASXL1, ASXL2 and ASXL3: a convergence of proteomics and epigenetics for translational medicine. Expert review of proteomics 52 25835095
2015 ASXL2 promotes proliferation of breast cancer cells by linking ERα to histone methylation. Oncogene 44 26640146
2017 Loss of Asxl2 leads to myeloid malignancies in mice. Nature communications 27 28593990
2012 Maintenance of adult cardiac function requires the chromatin factor Asxl2. Journal of molecular and cellular cardiology 25 23046516
2018 Clinical significance of ASXL2 and ZBTB7A mutations and C-terminally truncated RUNX1-RUNX1T1 expression in AML patients with t(8;21) enrolled in the JALSG AML201 study. Annals of hematology 24 30251205
2022 CARM1-mediated methylation of ASXL2 impairs tumor-suppressive function of MLL3/COMPASS. Science advances 16 36197977
2020 Myeloid-specific Asxl2 deletion limits diet-induced obesity by regulating energy expenditure. The Journal of clinical investigation 15 32310225
2013 Reciprocal regulation of LXRα activity by ASXL1 and ASXL2 in lipogenesis. Biochemical and biophysical research communications 15 24321552
2020 Association between serum anti‑ASXL2 antibody levels and acute ischemic stroke, acute myocardial infarction, diabetes mellitus, chronic kidney disease and digestive organ cancer, and their possible association with atherosclerosis and hypertension. International journal of molecular medicine 13 32945427
2021 Identification of Candidate Biomarker ASXL2 and Its Predictive Value in Pancreatic Carcinoma. Frontiers in oncology 10 34692512
2014 WTIP interacts with ASXL2 and blocks ASXL2-mediated activation of retinoic acid signaling. Biochemical and biophysical research communications 9 25065743
2022 A de novo and novel nonsense variants in ASXL2 gene is associated with Shashi-Pena syndrome. European journal of medical genetics 8 35182806
2020 Role of Asxl2 in non‑alcoholic steatohepatitis‑related hepatocellular carcinoma developed from diabetes. International journal of molecular medicine 8 33155659
2022 Prepubertal onset of type 2 diabetes in Shashi-Pena syndrome due to ASXL2 mutation. American journal of medical genetics. Part A 4 35716351
2023 A newborn with a pathogenic variant in ASXL2 expanding the phenotype of SHAPNS: a case report and literature review. Translational pediatrics 3 36798937
2023 Identification of a de novo variant in the ASXL2 gene related to Shashi-Pena syndrome. Molecular genetics & genomic medicine 3 37493007
2022 ASXL2 mutated myelodysplastic syndrome in a novel germline G6b variant. Leukemia research reports 3 35330689
2019 Secondary acquisition of BCR-ABL1 fusion in de novo GATA2-MECOM positive acute myeloid leukemia with subsequent emergence of a rare KMT2A-ASXL2 fusion. Cancer genetics 3 31902694
2023 Epigenetic Regulator ASXL2: Structure, Function and its Predictive Value in Diseases. Current protein & peptide science 1 36503466
2026 Chronic Hypoxia Disrupts Spermatogenesis Through ASXL2-EZH2-Mediated Microtubule Destabilization. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41782374
2025 ASXL2 Modulates Chromatin Remodeling to Direct Osteogenesis and Multiple Cell Fate in hPDLSCs. International dental journal 0 40680514
2024 Integrative analysis of ASXL family genes reveals ASXL2 as an immunoregulatory molecule in head and neck squamous cell carcinoma. Scientific reports 0 39732849
2024 Clinical Variability of Shashi-Pena Syndrome: A Novel ASXL2 Variant Associated with Overgrowth and Minor Neurodevelopmental Features. Molecular syndromology 0 40475172
2016 [Frequency and clinical features of ASXL2 gene mutation in acute myeloid leukemia patients with AML1- ETO fusion gene positive]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 0 27587249

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