Affinage

CFDP1

Heterochromatin-stabilizing protein CFDP1 · UniProt Q9UEE9

Length
299 aa
Mass
33.6 kDa
Annotated
2026-06-09
30 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CFDP1 (BCNT/Yeti) is an evolutionarily conserved chromatin factor that links histone variant deposition to chromosome organization and mitotic spindle assembly (PMID:24652835, PMID:28367969, PMID:38630655). It is a required activating subunit of the SRCAP (SWR1-class) chromatin remodeling complex: CFDP1 associates with SRCAP-C in a salt-sensitive manner, stimulates the complex's basal ATPase activity, and is necessary to restore genome-wide deposition of histone variant H2A.Z, with its loss reducing H2A.Z, H3K27me3, and H3K4me3 and derepressing developmental genes (PMID:41278978, PMID:28367969). The conserved BCNT domain mediates chromatin binding and homodimerization (PMID:24652835, PMID:27151176). At centromeric heterochromatin, CFDP1 colocalizes with satellite repeats and is required for the structural stability of CENPA, HP1α, and H2A.Z; this stabilization supports RCC1 binding, RanGTP production, and chromatin-mediated microtubule nucleation, a defect partially rescued by depleting the H2A.Z chaperone ANP32E (PMID:38630655). Independently, CFDP1 acts as a bipartite microtubule-associated protein in which the acidic N-terminus dissociates importin α from TPX2 to promote Aurora A activation while the basic C-terminus binds tubulin and drives microtubule bundling and polymerization (PMID:41683788). Consistent with these roles in cell division, CFDP1 loss causes cell-cycle and chromosome-segregation defects across HeLa cells, zebrafish, and mice, with embryonic lethality, gastrulation and spindle defects in mouse knockouts and cardiac and craniofacial defects in lower vertebrates (PMID:41683788, PMID:33987914, PMID:38630655, PMID:37566073). CFDP1 is regulated by phosphorylation (CKII, Ser250) and acetylation (CBP, including Lys268), and is a direct transcriptional target of TFII-I in neural crest progenitors (PMID:26182435, PMID:23145914).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 Medium

    Established the basic biochemical character of CFDP1/BCNT, showing it is a nuclear-and-cytosolic phosphoprotein, the first clue that it is a regulated, post-translationally modified factor.

    Evidence Subcellular fractionation, immunohistochemistry, and in vitro casein kinase II assay on bovine/human BCNT

    PMID:10350657

    Open questions at the time
    • No functional role assigned
    • Physiological kinase and consequence of phosphorylation unknown
  2. 2003 Medium

    Tested whether CFDP1 has a cytoskeletal/transport role, linking the Drosophila ortholog YETI directly to kinesin-I motor subunits and hinting at a non-chromatin function.

    Evidence Yeast two-hybrid and copurification from Drosophila S2 cells, immunostaining

    PMID:14720462

    Open questions at the time
    • Functional significance of kinesin binding not established
    • Not validated in mammalian cells
  3. 2014 High

    Identified CFDP1's core chromatin function by showing the YETI ortholog binds chromatin through its BCNT domain and is required for H2A.V deposition via interaction with the DOM/Tip60 remodeling machinery.

    Evidence Co-IP, chromatin binding assays, RNAi loss-of-function and polytene immunostaining in Drosophila

    PMID:24652835

    Open questions at the time
    • Mechanism of H2A.V deposition stimulation not defined
    • Whether mammalian CFDP1 acts identically not shown
  4. 2015 High

    Mapped the post-translational modification landscape of CFDP1, defining Ser250 phosphorylation and lysine acetylation by CBP within the conserved BCNT-C domain.

    Evidence Deletion/substitution mutagenesis, mass spectrometry phosphosite mapping, in vitro acetylation with CBP

    PMID:26182435

    Open questions at the time
    • Functional consequence of each PTM on chromatin activity unknown
    • In vivo enzymes for acetylation not confirmed
  5. 2016 Medium

    Showed that CFDP1 homodimerizes via the BCNT domain and that YETI/CFDP1 heterodimers are inactive, explaining the dominant-negative behavior and implicating dimerization in regulation.

    Evidence GST pull-down and in vivo dominant-negative expression in Drosophila

    PMID:27151176

    Open questions at the time
    • Structural basis of dimerization not resolved
    • Whether dimerization gates complex assembly unknown
  6. 2017 High

    Translated the chromatin role to human cells, linking CFDP1 to the SRCAP complex and showing depletion disrupts chromosome organization, condensin recruitment, and cell cycle progression.

    Evidence RNAi, reciprocal Co-IP, chromatin fractionation, immunofluorescence and cell cycle analysis in HeLa cells

    PMID:28367969

    Open questions at the time
    • Whether CFDP1 is a stable vs. transient SRCAP subunit not resolved
    • Mechanism connecting H2A.Z to condensin loading unknown
  7. 2021 Medium

    Defined the developmental consequence of CFDP1 loss, showing G2/M delay, p53-dependent apoptosis, and failed neural progenitor differentiation in zebrafish.

    Evidence Zebrafish cfdp1 mutant analysis with pH3 staining, apoptosis assays, tp53 rescue

    PMID:33987914

    Open questions at the time
    • Molecular cause of mitotic block not pinpointed
    • Link to chromatin defect not directly tested
  8. 2023 Medium

    Extended CFDP1 function to organogenesis by showing its loss causes cardiac arrhythmia and valve defects through downregulation of Wnt (but not Notch) signaling.

    Evidence Morpholino and CRISPR loss-of-function in zebrafish with cardiac imaging and pathway reporters

    PMID:37566073

    Open questions at the time
    • How CFDP1 chromatin activity feeds into Wnt regulation unknown
    • Direct vs. indirect effect on Wnt genes not distinguished
  9. 2024 High

    Connected CFDP1's chromatin role to spindle assembly, showing it stabilizes centromeric heterochromatin to enable RCC1/RanGTP-driven microtubule nucleation, with ANP32E depletion rescuing the H2A.Z and developmental defects.

    Evidence Colocalization imaging, ChIP, RanGTP assays, microtubule nucleation assays, ANP32E epistasis rescue in cells and mice

    PMID:38630655

    Open questions at the time
    • Direct vs. H2A.Z-mediated effect on RCC1 binding not fully separated
    • Whether SRCAP activity is required at centromeres not tested
  10. 2025 High

    Provided the biochemical mechanism for CFDP1 in chromatin remodeling, reconstituting SRCAP-C and showing CFDP1 is required to stimulate its ATPase activity and H2A.Z dimer exchange, with genome-wide consequences for H2A.Z and developmental gene marks.

    Evidence In vitro SRCAP-C reconstitution, H2A.Z exchange and ATPase assays, CFDP1 KO hiPSC ChIP-seq (preprint)

    PMID:41278978

    Open questions at the time
    • Structural basis of ATPase stimulation not solved
    • Stoichiometry and regulation of CFDP1 within SRCAP-C unclear
  11. 2025 Medium

    Resolved a long-standing localization ambiguity, demonstrating by live imaging that CFDP1 is predominantly nuclear and that the cytoplasmic fraction recovered biochemically is a fractionation artifact of its disordered properties.

    Evidence Live-cell fluorescence imaging, detergent vs. digitonin fractionation, quantitative LC-MS/MS in C2C12 cells (preprint)

    PMID:bio_10.1101_2025.04.28.651124

    Open questions at the time
    • Reconciliation with reported cytosolic spindle/tubulin functions unaddressed
    • Single cell-line context
  12. 2026 High

    Defined CFDP1 as a bipartite microtubule-associated protein, separating an N-terminal importin α/TPX2-dissociating activity that promotes Aurora A activation from a C-terminal tubulin-binding, microtubule-bundling activity, and tied loss to gastrulation defects and embryonic lethality in mice.

    Evidence Mouse knockout phenotyping, domain dissection, importin α–TPX2 dissociation assay, tubulin binding and microtubule polymerization assays

    PMID:41683788

    Open questions at the time
    • How chromatin and cytoplasmic MAP functions are coordinated unknown
    • Regulation of N- vs C-terminal activities during the cell cycle unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how CFDP1's chromatin-remodeling role within SRCAP, its centromeric heterochromatin stabilization, and its direct microtubule-associated activity are mechanistically integrated within a single cell cycle.
  • No structure of CFDP1 within SRCAP-C
  • Spatial/temporal partitioning between nuclear and spindle pools undefined
  • Direct CFDP1–NEDD4/PTEN mechanism in cancer not validated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0098772 molecular function regulator activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 3 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-1266738 Developmental Biology 3 R-HSA-4839726 Chromatin organization 3
Complex memberships
SRCAP complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 Drosophila YETI (ortholog of CFDP1) binds to polytene chromosomes through its conserved BCNT domain, physically interacts with histone variant H2A.V, HP1a, and the ATPase subunit Domino-A (DOM-A) of the DOM/Tip60 chromatin remodeling complex, and is required for H2A.V accumulation at chromatin sites. Loss of YETI causes lethality and severe defects in higher-order chromatin organization including impaired association of H2A.V, nucleosomal histones, and epigenetic marks with polytene chromosomes. YETI was identified as a downstream target of DOM-A. Co-immunoprecipitation, chromatin binding assays, RNAi/genetic loss-of-function, immunostaining of polytene chromosomes Journal of cell science High 24652835
2017 Human CFDP1 binds to chromatin and interacts with subunits of the SRCAP chromatin remodeling complex. RNAi-mediated depletion of CFDP1 in HeLa cells causes chromosome organization defects, impaired SMC2 condensin recruitment, and cell cycle progression defects. RNAi knockdown, Co-immunoprecipitation, chromatin fractionation, immunofluorescence, cell cycle analysis Scientific reports High 28367969
2016 Both Drosophila YETI and human CFDP1 undergo homodimerization mediated by the BCNT domain. YETI and CFDP1 physically interact with each other to form inactive heterodimers, which underlies the dominant-negative effect of CFDP1 expression in flies. GST pull-down assays, in vivo expression in Drosophila with phenotypic analysis Scientific reports Medium 27151176
2003 Drosophila YETI (CFDP1 ortholog) binds specifically to both the kinesin light chain (via tetratricopeptide repeats) and the kinesin heavy chain (amino acids 675–975) subunits of kinesin-I, as shown by yeast two-hybrid and copurification from S2 cells. YETI localizes to both nucleus and cytosol. Yeast two-hybrid screen, copurification assay from Drosophila S2 cells, immunostaining Biology of the cell Medium 14720462
2015 Mammalian Bcnt/Cfdp1 has an acidic stretch in its disordered N-terminal region that causes anomalous gel mobility on SDS-PAGE. Ser250 in the conserved BCNT-C domain is heavily phosphorylated in vivo and is a major determinant of the protein's electrophoretic behavior. Four lysine residues including Lys268 in BCNT-C are acetylated in vivo, and Bcnt/Cfdp1 is acetylated in vitro by CREB-binding protein (CBP). Bovine and human BCNTs are phosphorylated by casein kinase II in vitro. Deletion mutant expression in E. coli and HEK cells, phosphatase treatment, Ser250 substitution mutagenesis, mass spectrometry-based phosphosite mapping, in vitro acetylation assay with CBP Bioscience reports High 26182435
1999 Bovine BCNT (Cfdp1 ortholog) shows partial nuclear localization as determined by subcellular fractionation and immunohistochemistry in bovine epithelial cells and brain tissue, with a significant nuclear fraction and a major cytosolic portion. Bovine BCNT is a phosphoprotein, and both bovine and human BCNTs are phosphorylated by casein kinase II in vitro. Subcellular fractionation, immunohistochemistry, in vitro kinase assay with casein kinase II Biochimica et biophysica acta Medium 10350657
2024 CFDP1 colocalizes with heterochromatin at major and minor satellite repeats and is essential for structural stability of centromeric heterochromatin including CENPA, HP1α, and H2A.Z. Loss of CFDP1 reduces RCC1 binding to satellite repeats, decreasing RanGTP levels and impairing chromatin-mediated microtubule nucleation at the onset of mitotic spindle formation. Knockdown of histone chaperone ANP32E in CFDP1-deficient cells/mice partially rescued H2A.Z levels, RanGTP, craniofacial defects, and microtubule nucleation. Co-localization imaging, ChIP, RanGTP activity assays, genetic rescue experiments (ANP32E knockdown in CFDP1 KO cells and mice), microtubule nucleation assays PLoS biology High 38630655
2025 CFDP1 weakly associates with the human SRCAP complex (SRCAP-C) in a salt-concentration-dependent manner. SRCAP-C purified under high-salt conditions lacks CFDP1 and is inactive for H2A.Z dimer exchange; addition of exogenous CFDP1 restores H2A.Z deposition activity of SRCAP-C. CFDP1 stimulates the basal ATPase activity of reconstituted SRCAP-C. CFDP1 deficiency in hiPSCs causes genome-wide reduction of H2A.Z, H3K27me3, and H3K4me3 deposition and upregulation of developmental genes normally marked by these modifications. Biochemical reconstitution of SRCAP-C, in vitro H2A.Z dimer exchange assay, ATPase activity assay, CFDP1 KO in hiPSCs with ChIP-seq bioRxivpreprint High 41278978
2026 CFDP1 functions as a bipartite microtubule-associated protein (MAP): its acidic N-terminus harbors a nuclear localization signal required for dissociation of importin α from the spindle assembly factor TPX2 (thereby promoting Aurora A kinase activation and microtubule nucleation), while its basic C-terminus interacts with tubulin, co-localizes with the mitotic spindle, and promotes microtubule bundling and polymerization. Loss of CFDP1 in mice causes gastrulation defects and embryonic lethality at e8.5 associated with chromosome segregation spindle defects and loss of K-fiber stability. Mouse CFDP1 knockout (phenotypic analysis), domain dissection with N-terminal/C-terminal constructs, importin α–TPX2 dissociation assay, tubulin-binding assay, microtubule bundling/polymerization assay, co-localization with mitotic spindle International journal of molecular sciences High 41683788
2021 In zebrafish, loss of Cfdp1 (cfdp1 mutants) causes G2-to-M phase cell cycle delay, mitotic block before anaphase (despite normal spindle formation), increased apoptosis (via tp53-dependent pathway), and failure of neural progenitor differentiation in the cerebellum and retina, accompanied by elevated cyclin B1 expression. Zebrafish cfdp1 mutant analysis, phospho-histone H3 staining, apoptosis assays, tp53 inhibition rescue, cyclin B1 expression analysis Developmental dynamics Medium 33987914
2023 In zebrafish, cfdp1 loss-of-function (morpholino knockdown and CRISPR knockout) causes arrhythmic hearts with defective cardiac performance and lethality. Mechanistically, cfdp1 abrogation downregulates Wnt signaling in embryonic hearts during valve development without affecting Notch activation. Morpholino knockdown, CRISPR knockout in zebrafish, cardiac function imaging, Wnt and Notch pathway reporter/expression analysis Cells Medium 37566073
2022 CFDP1 promotes hepatocellular carcinoma malignancy via NEDD4-mediated ubiquitination and degradation of PTEN, leading to activation of the PI3K/AKT signaling pathway, as demonstrated by western blotting in HCC cell lines and in vivo tumor models. Western blotting, in vitro and in vivo loss/gain-of-function experiments in HCC cells, GSEA/GeneCards pathway analysis, xenograft mouse model Cancer medicine Low 35861040
2012 TFII-I transcription factors (GTF2I/GTF2IRD1) are directly recruited to the promoter of CFDP1 in human neural crest progenitor cells, identifying CFDP1 as a direct transcriptional target of TFII-I. ChIP-chip (chromatin immunoprecipitation with tiling promoter arrays) in human neural crest progenitor cells The Cleft palate-craniofacial journal Medium 23145914
2025 In C2C12 myoblasts, fluorescent protein-tagged Bcnt/Cfdp1 localizes predominantly to the nucleus, preferentially in low-DAPI-density regions, and this localization persists in differentiated myotubes. However, detergent-based biochemical fractionation consistently recovers a substantial fraction in the cytoplasm, an artifact attributed to the elastic/disordered properties of Bcnt/Cfdp1 causing artifactual translocation during fractionation under macromolecular crowding conditions. Live-cell fluorescence imaging of tagged Bcnt/Cfdp1, detergent-based subcellular fractionation, digitonin-based fractionation, quantitative proteomics (LC-MS/MS) of fractions bioRxivpreprint Medium bio_10.1101_2025.04.28.651124

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Identification of the BCAR1-CFDP1-TMEM170A locus as a determinant of carotid intima-media thickness and coronary artery disease risk. Circulation. Cardiovascular genetics 40 23152477
2014 Yeti, an essential Drosophila melanogaster gene, encodes a protein required for chromatin organization. Journal of cell science 29 24652835
2017 The human Cranio Facial Development Protein 1 (Cfdp1) gene encodes a protein required for the maintenance of higher-order chromatin organization. Scientific reports 24 28367969
2003 A transposable element-mediated gene divergence that directly produces a novel type bovine Bcnt protein including the endonuclease domain of RTE-1. Molecular biology and evolution 24 12832649
2013 The biogeography of the yeti crabs (Kiwaidae) with notes on the phylogeny of the Chirostyloidea (Decapoda: Anomura). Proceedings. Biological sciences 22 23782878
2017 Evolutionary history of enigmatic bears in the Tibetan Plateau-Himalaya region and the identity of the yeti. Proceedings. Biological sciences 19 29187630
1998 Existence of a bovine LINE repetitive insert that appears in the cDNA of bovine protein BCNT in ruminant, but not in human, genomes. Gene 19 9602175
2014 The Bucentaur (BCNT) protein family: a long-neglected class of essential proteins required for chromatin/chromosome organization and function. Chromosoma 17 25547403
2000 Yeti--a degenerate gypsy-like LTR retrotransposon in the filamentous ascomycete Podospora anserina. Current genetics 15 11057446
2022 CFDP1 promotes hepatocellular carcinoma progression through activating NEDD4/PTEN/PI3K/AKT signaling pathway. Cancer medicine 14 35861040
2015 Mammalian Bcnt/Cfdp1, a potential epigenetic factor characterized by an acidic stretch in the disordered N-terminal and Ser250 phosphorylation in the conserved C-terminal regions. Bioscience reports 13 26182435
2012 ChIP-Chip Identifies SEC23A, CFDP1, and NSD1 as TFII-I Target Genes in Human Neural Crest Progenitor Cells. The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 13 23145914
2016 Expression of human Cfdp1 gene in Drosophila reveals new insights into the function of the evolutionarily conserved BCNT protein family. Scientific reports 12 27151176
2019 The True Story of Yeti, the "Abominable" Heterochromatic Gene of Drosophila melanogaster. Frontiers in physiology 10 31507454
2017 Functional analysis of the cfdp1 gene in zebrafish provides evidence for its crucial role in craniofacial development and osteogenesis. Experimental cell research 10 29107067
2003 The Drosophila kinesin-I associated protein YETI binds both kinesin subunits. Biology of the cell 10 14720462
2014 Genetic analysis of hair samples attributed to yeti, bigfoot and other anomalous primates. Proceedings. Biological sciences 9 24990672
1999 Partial nuclear localization of a bovine phosphoprotein, BCNT, that includes a region derived from a LINE repetitive sequence in Ruminantia. Biochimica et biophysica acta 9 10350657
2021 Cfdp1 controls the cell cycle and neural differentiation in the zebrafish cerebellum and retina. Developmental dynamics : an official publication of the American Association of Anatomists 8 33987914
2022 CFDP1 is a neuroblastoma susceptibility gene that regulates transcription factors of the noradrenergic cell identity. HGG advances 6 36425957
2017 The complete mitochondrial genome of a yeti crab Kiwa tyleri Thatje, 2015 (Crustacea: Decapod: Anomura: Kiwaidae) from deep-sea hydrothermal vent. Mitochondrial DNA. Part B, Resources 5 33473745
2014 On the evolution of Yeti, a Drosophila melanogaster heterochromatin gene. PloS one 5 25405891
2001 Gene organization of bovine BCNT that contains a portion corresponding to an endonuclease domain derived from an RTE-1 (Bov-B LINE), non-LTR retrotransposable element: duplication of an intramolecular repeat unit downstream of the truncated RTE-1. Gene 5 11368901
2020 Influence of sequence length and charged residues on Swc5 binding with histone H2A-H2B. Proteins 4 33320380
2024 CFDP1 regulates the stability of pericentric heterochromatin thereby affecting RAN GTPase activity and mitotic spindle formation. PLoS biology 3 38630655
2023 Cfdp1 Is Essential for Cardiac Development and Function. Cells 3 37566073
2020 Overcoming off-targets: assessing Western blot signals for Bcnt/Cfdp1, a tentative component of the chromatin remodeling complex. Bioscience reports 2 32432658
2026 The Chromatin Protein CFDP1 Activates TPX2 and Promotes Chromosomal Microtubule Nucleation and Spindle Assembly. International journal of molecular sciences 1 41683788
2025 The Chromatin Protein CFDP1 Activates TPX2 and Promotes Chromosomal Microtubule Nucleation and Spindle Assembly. bioRxiv : the preprint server for biology 0 41040403
2025 CFDP1 is required for histone variant H2A.Z deposition by the human SRCAP chromatin remodeling complex. bioRxiv : the preprint server for biology 0 41278978

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