KAT14

KAT14 (ATAC2/CRP2BP) is a histone acetyltransferase that serves as both a catalytic and an architectural subunit of the ATAC chromatin-modifying complex, where it acetylates histone H4 and, in specific gene contexts, H3K9 and H3K18 to control transcription, development, and cell-cycle progression (PMID:18327268, PMID:19103755). Within ATAC its enzymatic activity preferentially targets H4K16 in vivo, while ATAC2 itself is required for complex integrity—its loss disassembles the mammalian ATAC complex—and the assembled complex does not remodel nucleosomes directly but stimulates the sliding activity of ISWI, SWI-SNF, and RSC remodelers (PMID:18327268, PMID:19103755). Targeted disruption in mice establishes that KAT14 is essential for embryonic development, normal histone acetylation, cell-cycle progression, and the prevention of embryonic apoptosis (PMID:19103755). Beyond its core ATAC role, KAT14 directly interacts with serum response factor (SRF) and deposits activating histone acetylation at target promoters, driving α-SMA expression during TGF-β-induced myofibroblast differentiation and activating CDH5 (VE-cadherin) via H3K9/H3K18 acetylation in trophoblasts, where trophoblast-specific knockout produces preeclampsia-like phenotypes rescued by CDH5 (PMID:38867256, PMID:41867034). Its enzymatic activity is regulated by direct binding of nuclear actin (PMID:30890647), and KAT14 is SUMOylated at K408 (PMID:29234079).

1. 2008 High

   Established that KAT14/Atac2 is a catalytic histone acetyltransferase subunit of the ATAC complex, defining its core molecular activity and its preference for histone H4.

   Evidence MudPIT identification of ATAC subunits, in vitro HAT assay with recombinant Atac2, and Drosophila embryo mutant analysis showing loss of H4K16 acetylation

   PMID:18327268

   Open questions at the time

   • Mechanism by which H4K16 is selected over other H4 lysines not resolved
   • Contribution of the second ATAC HAT subunit (GCN5) vs Atac2 to bulk acetylation not partitioned
2. 2008 High

   Showed the ATAC complex does not itself remodel nucleosomes but functionally couples histone acetylation to ATP-dependent remodeling, situating KAT14 upstream of chromatin remodelers.

   Evidence In vitro nucleosome-sliding assays with purified ATAC and ISWI, SWI-SNF, and RSC complexes

   PMID:18327268

   Open questions at the time

   • Whether KAT14 catalytic activity is required for remodeler stimulation not isolated
   • In vivo relevance of the ATAC-remodeler coupling not tested
3. 2008 High

   Demonstrated KAT14 has a dual role—weak intrinsic HAT activity plus an architectural function required for ATAC complex assembly—and is essential for mammalian development.

   Evidence In vitro HAT assay with recombinant mammalian ATAC2, knockdown/knockout complex-stability analysis, and targeted Atac2 disruption in mice with embryonic cell-cycle and apoptosis phenotypes

   PMID:19103755

   Open questions at the time

   • Separation of catalytic from architectural contribution to the embryonic phenotype not achieved
   • Direct genomic targets driving cell-cycle/apoptosis defects not mapped
4. 2012 Low

   Predicted a PWAPA (PHD-like finger plus winged-helix) cassette in KAT14 that could mediate combined DNA and histone-methylation recognition, offering a candidate chromatin-targeting module.

   Evidence Sensitive sequence analysis and 3D modeling on the solved ASH2L PWAPA structure

   PMID:22664638

   Open questions at the time

   • Purely computational with no experimental validation of PWAPA binding in KAT14
   • No demonstrated DNA or methyl-mark binding by the predicted domain
5. 2013 Medium

   Linked KAT14 activity to tissue stem-cell control by showing Atac2 dosage tunes intestinal stem cell number versus differentiation in vivo.

   Evidence Drosophila intestinal RNAi, dominant-negative, and overexpression experiments scoring ISC homeostasis

   PMID:23535028

   Open questions at the time

   • Molecular targets in ISCs not identified
   • Whether the effect requires HAT activity not tested
6. 2017 Medium

   Identified a post-translational regulatory mark by mapping SUMOylation of KAT14 at K408.

   Evidence Split fluorescent protein reconstitution SUMOylation screen in living mammalian cells with site mapping

   PMID:29234079

   Open questions at the time

   • Functional consequence of K408 SUMOylation on HAT activity or localization unknown
   • Single method for site validation
7. 2019 High

   Revealed nuclear actin as a direct binding partner and regulator of KAT14 enzymatic activity, connecting actin dynamics to ATAC-mediated acetylation and potentially to co-transcriptional splicing.

   Evidence AP-MS and BioID, direct binding assays, and in vitro plus cell-based HAT activity measurements with altered actin; minigene splicing assays

   PMID:30890647

   Open questions at the time

   • The actin-binding interface on KAT14 not defined
   • Causal link from KAT14 to splicing remains indirect via actin/elongation
8. 2023 Medium

   Showed KAT14 acts as a HAT-independent adaptor, stabilizing the CRP2/MRTF/SRF/CArG-box complex to promote smooth-muscle gene expression, distinguishing a non-enzymatic function from its acetyltransferase role.

   Evidence Cell-based CRP2BP expression-modulation assays, SMC gene expression analysis, and collagen adhesion/p38MAPK experiments

   PMID:37899269

   Open questions at the time

   • Mechanism rests on expression readouts rather than reconstituted biochemistry
   • Direct CRP2BP-MRTF/SRF contacts not structurally defined
9. 2024 High

   Established a catalytic KAT14/SRF axis in which KAT14 acetylates H4 at the α-SMA promoter to drive TGF-β-induced myofibroblast differentiation and ECM production.

   Evidence Reciprocal Co-IP, ChIP for H4 acetylation at the α-SMA promoter, loss/gain-of-function in cells, and AAV-mediated Kat14 knockdown in a mouse endometriosis model

   PMID:38867256

   Open questions at the time

   • How SRF recruits KAT14 to specific promoters not resolved
   • Genome-wide SRF-dependent KAT14 targets not mapped
10. 2026 High

    Extended the KAT14/SRF mechanism to vascular biology, showing KAT14 activates CDH5 via H3K9/H3K18 acetylation in trophoblasts and is required to prevent preeclampsia-like pathology.

    Evidence Co-IP, EMSA, luciferase reporters, ChIP for H3K9/H3K18 acetylation, RNA-seq, conditional trophoblast- and CDH5-Cre KAT14 knockout mice, and CDH5 rescue

    PMID:41867034

    Open questions at the time

    • Switch between H4 (α-SMA) and H3K9/H3K18 (CDH5) target specificity not explained
    • Whether ATAC-complex context is required at these loci not addressed

• How KAT14 selects its histone-target residues and is recruited to specific promoters across the ATAC complex versus SRF-cooperative and CRP2-adaptor contexts remains unresolved.
• No structural model of KAT14 substrate selection
• Determinants partitioning HAT-dependent versus adaptor functions undefined
• Genome-wide direct binding map of KAT14 lacking