Affinage

PWWP2A

PWWP domain-containing protein 2A · UniProt Q96N64

Length
755 aa
Mass
82.0 kDa
Annotated
2026-06-10
16 papers in source corpus 6 papers cited in narrative 7 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

PWWP2A is a multivalent chromatin-binding protein that links the histone variant H2A.Z to histone deacetylase activity to control transcriptional fidelity and vertebrate development (PMID:28645917, PMID:30327463). It engages chromatin through distinct domains: two internal regions confer selective binding to H2A.Z-containing nucleosomes, with the H2A.Z C-terminal tail acting as a key recruitment determinant, while the PWWP domain mediates direct binding to free linker DNA and to H3K36me3-containing nucleosomes (PMID:28645917, PMID:30327463). In vivo it concentrates at H2A.Z-marked promoters of highly transcribed genes and more weakly over H3K36me3-marked gene bodies (PMID:28645917, PMID:30327463). PWWP2A recruits an MTA1-specific NuRD deacetylase subcomplex (M1HR; MTA1–HDAC1–RBBP4/7) that excludes CHD, GATAD2, and MBD subunits, and its loss raises H3K27 and H2A.Z acetylation, reflecting failed M1HR delivery to chromatin (PMID:30327463). By competing with MBD proteins for the shared MTA–HDAC–RBBP deacetylase module, PWWP2A acts as a switch governing NuRD composition (PMID:33264611). Functionally, PWWP2A (with PWWP2B) suppresses spurious intragenic transcription initiation in a manner analogous to the yeast H3K36me3/Rpd3S pathway, restraining initiating Pol-II and histone acetylation within gene bodies (PMID:33235983), and it is required for proper mitotic progression (PMID:28645917) and for neural crest cell differentiation and craniofacial development (PMID:28645917). HMG20A and ZNF512B are additional components of the H2A.Z/PWWP2A chromatin-modifying network, with HMG20A loss phenocopying PWWP2A depletion in vivo (PMID:36709316, PMID:39460621).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2017 High

    Established PWWP2A as a dedicated H2A.Z-nucleosome reader, answering how a specific factor distinguishes the H2A.Z variant from canonical H2A in chromatin.

    Evidence H2A.Z interactome co-IP/MS, ChIP-seq, domain mutagenesis, and siRNA knockdown with mitotic readout in cells and Xenopus

    PMID:28645917

    Open questions at the time
    • Structural basis for H2A.Z C-terminal tail recognition not resolved
    • Downstream effector of mitotic delay not defined at this stage
  2. 2017 High

    Linked PWWP2A to vertebrate morphogenesis, showing the chromatin reader is required for neural crest differentiation/migration and craniofacial formation.

    Evidence Xenopus morpholino knockdown with craniofacial and neural crest phenotyping

    PMID:28645917

    Open questions at the time
    • Molecular target genes driving the neural crest phenotype not mapped
    • Connection between developmental defect and biochemical activity not yet established
  3. 2018 High

    Defined the effector arm: PWWP2A reads multiple chromatin features and recruits a specific NuRD deacetylase subcomplex (M1HR) to control histone acetylation.

    Evidence In vitro binding assays, ChIP-seq, co-IP/MS, and siRNA knockdown with H3K27/H2A.Z acetylation readout

    PMID:30327463

    Open questions at the time
    • Whether M1HR recruitment fully accounts for developmental/mitotic phenotypes not shown
    • Quantitative contribution of DNA vs H3K36me3 vs H2A.Z binding to in vivo targeting unresolved
  4. 2020 High

    Provided a mechanistic switch model: PWWP2A competes with MBD proteins for the MTA-HDAC-RBBP module, controlling NuRD complex composition.

    Evidence Quantitative MS, cross-linking, and EM of native mammalian NuRD complex

    PMID:33264611

    Open questions at the time
    • In vivo dynamics and regulation of the competition not characterized
    • Genome-wide consequences of the compositional switch not directly profiled
  5. 2020 High

    Assigned a transcriptional-fidelity function, showing PWWP2A/B as H3K36me3 readers that suppress spurious intragenic initiation, analogous to yeast Rpd3S.

    Evidence CAGE-seq with histone acetylation and Pol-II ChIP-seq in WT vs PWWP2A/B DKO mESCs

    PMID:33235983

    Open questions at the time
    • Redundancy and division of labor between PWWP2A and PWWP2B not dissected
    • Direct demonstration that suppressed cryptic transcripts arise from M1HR loss not shown
  6. 2023 High

    Expanded the network by identifying HMG20A as a functional partner whose loss phenocopies PWWP2A depletion, linking the axis to EMT and differentiation programs.

    Evidence Co-IP/MS, Xenopus morpholino knockdown, mESC differentiation, ATAC-seq, and RNA-seq

    PMID:36709316

    Open questions at the time
    • Direct physical contacts within the PWWP2A-HMG20A-NuRD assembly not mapped
    • Whether HMG20A acts within M1HR or a distinct subassembly unresolved
  7. 2024 Medium

    Added ZNF512B as a further associated component of the H2A.Z/PWWP2A/HMG20A chromatin network.

    Evidence Co-IP/MS placing ZNF512B in the H2A.Z/PWWP2A/HMG20A complex

    PMID:39460621

    Open questions at the time
    • Single co-IP/MS without reciprocal validation or functional follow-up on PWWP2A
    • Role of ZNF512B in PWWP2A-dependent functions undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PWWP2A integrates its multivalent chromatin readout to selectively deliver M1HR at specific loci, and how this is coordinated across mitosis, transcriptional fidelity, and development, remains unresolved.
  • No structure of PWWP2A bound to H2A.Z-nucleosome or to M1HR
  • Causal chain from chromatin binding to mitotic and developmental phenotypes incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 3 GO:0003677 DNA binding 2 GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 2
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-1266738 Developmental Biology 2 R-HSA-74160 Gene expression (Transcription) 1
Partners
HDAC1HMG20AMTA1PWWP2BRBBP4RBBP7ZNF512B
Complex memberships
NuRD (MTA1-specific M1HR subcomplex: MTA1-HDAC1-RBBP4/7)

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 PWWP2A is a novel H2A.Z-nucleosome binding protein identified through H2A.Z interactome analysis. Two internal protein regions mediate H2A.Z-specificity and nucleosome interaction, while the PWWP domain mediates direct DNA binding. PWWP2A binds selectively to H2A.Z-containing nucleosomes with strong preference for promoters of highly transcribed genes. The C-terminal tail of H2A.Z is one important mediator to recruit PWWP2A to chromatin. Depletion of PWWP2A impairs mitotic progression (mitotic delay) and does not influence H2A.Z occupancy. H2A.Z interactome (co-IP/MS), genome-wide mapping (ChIP-seq), domain mutagenesis, siRNA knockdown with cell proliferation/mitosis readout, Xenopus knockdown The EMBO journal High 28645917
2017 Knockdown of PWWP2A in Xenopus results in severe craniofacial defects arising from neural crest cell differentiation and migration problems, establishing a functional role in vertebrate development. Xenopus morpholino knockdown with phenotypic analysis of craniofacial structures and neural crest cell migration The EMBO journal High 28645917
2018 PWWP2A binds free linker DNA and H3K36me3-containing nucleosomes via distinct domains (in vitro). In vivo, PWWP2A strongly occupies H2A.Z-containing regulatory regions and weakly binds H3K36me3-containing gene bodies. PWWP2A interacts with an MTA1-specific subcomplex of the NuRD complex (M1HR) consisting of MTA1, HDAC1, and RBBP4/7, excluding CHD, GATAD2, and MBD proteins. Depletion of PWWP2A increases acetylation on H3K27 and H2A.Z, implicating impaired chromatin recruitment of M1HR. In vitro binding assays, ChIP-seq, co-IP/MS, siRNA knockdown with histone acetylation readout Nature communications High 30327463
2020 PWWP2A competes with MBD proteins for binding to the MTA-HDAC-RBBP subcomplex of NuRD, establishing a biochemical switching mechanism that regulates NuRD composition. The NuRD complex has an asymmetric architecture built from a 2:2:4 (MTA:HDAC:RBBP) deacetylase module and a 1:1:1 (MBD:GATAD2:CHD) remodeling module. Quantitative mass spectrometry, cross-linking, protein biochemistry, electron microscopy of native mammalian NuRD complex Cell reports High 33264611
2020 PWWP2A/B function as H3K36me3 readers that form a stable complex with HDAC1/2 and suppress spurious intragenic transcription initiation in mESCs, analogous to the yeast H3K36me3/Rpd3S pathway. Loss of PWWP2A/B enhances spurious intragenic initiation associated with increased initiating Pol-II and histone acetylation. CAGE-seq in wild-type vs. PWWP2A/B double-knockout (DKO) mESCs; histone acetylation and Pol-II ChIP-seq iScience High 33235983
2023 HMG20A is identified as a component of the H2A.Z/PWWP2A/NuRD axis. Depletion of Hmg20a in Xenopus phenocopies PWWP2A knockdown (craniofacial and heart defects), and loss of HMG20A causes chromatin accessibility changes and deregulation of EMT and differentiation transcription programs, placing HMG20A as part of the PWWP2A-associated chromatin-modifying network. Co-IP/MS identifying HMG20A in NuRD/PWWP2A complexes; Xenopus morpholino knockdown; mESC differentiation assays; ATAC-seq; RNA-seq Nature communications High 36709316
2024 ZNF512B was identified as a protein associated with H2A.Z, HMG20A, and PWWP2A, placing ZNF512B in the PWWP2A-associated chromatin network at H2A.Z-containing chromatin. Co-IP/MS identifying ZNF512B in the H2A.Z/PWWP2A/HMG20A complex Nucleic acids research Medium 39460621

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2023 Human umbilical cord mesenchymal stem cell-derived extracellular vesicles alleviated silica induced lung inflammation and fibrosis in mice via circPWWP2A/miR-223-3p/NLRP3 axis. Ecotoxicology and environmental safety 49 36646008
2018 PWWP2A binds distinct chromatin moieties and interacts with an MTA1-specific core NuRD complex. Nature communications 45 30327463
2017 Multivalent binding of PWWP2A to H2A.Z regulates mitosis and neural crest differentiation. The EMBO journal 45 28645917
2019 TGF-β- and lipopolysaccharide-induced upregulation of circular RNA PWWP2A promotes hepatic fibrosis via sponging miR-203 and miR-223. Aging 44 31719209
2020 The Nucleosome Remodeling and Deacetylase Complex Has an Asymmetric, Dynamic, and Modular Architecture. Cell reports 42 33264611
2020 Spitz Tumors With ROS1 Fusions: A Clinicopathological Study of 6 Cases, Including FISH for Chromosomal Copy Number Alterations and Mutation Analysis Using Next-Generation Sequencing. The American Journal of dermatopathology 41 31361613
2020 Clinical, morphologic, and genomic findings in ROS1 fusion Spitz neoplasms. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 34 32862201
2024 Comprehensive clinicopathological, molecular, and methylation analysis of mesenchymal tumors with NTRK and other kinase gene aberrations. The Journal of pathology 28 38332737
2022 Ferroptosis related genes participate in the pathogenesis of spinal cord injury via HIF-1 signaling pathway. Brain research bulletin 17 36414158
2023 The H2A.Z and NuRD associated protein HMG20A controls early head and heart developmental transcription programs. Nature communications 16 36709316
2020 The PWWP2A Histone Deacetylase Complex Represses Intragenic Spurious Transcription Initiation in mESCs. iScience 9 33235983
2021 ROS1 pattern of immunostaining in 11 cases of spitzoid tumour: comparison with histopathological, fluorescence in-situ hybridisation and next-generation sequencing analysis. Histopathology 6 34231248
2023 Circ_PWWP2A promotes lung fibroblast proliferation and fibrosis via the miR-27b-3p/GATA3 axis, thereby aggravating idiopathic pulmonary fibrosis. Acta biochimica Polonica 5 37672715
2025 PWWP2A/B: Prominent players in the proteomic landscape. Gene 1 39809369
2024 ZNF512B binds RBBP4 via a variant NuRD interaction motif and aggregates chromatin in a NuRD complex-independent manner. Nucleic acids research 1 39460621
2023 Two High-Quality Cygnus Genome Assemblies Reveal Genomic Variations Associated with Plumage Color. International journal of molecular sciences 1 38069278

Missed literature

Know a paper Affinage missed for PWWP2A? Flag it for the maintainers and the community.

No submissions yet.