Divergent Functions of Histone Acetyltransferase Paralogs KAT2A and KAT2B in Keratinocyte Stemness and Differentiation
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PROVIDER: PRJNA889419 | ENA |
REPOSITORIES: ENA
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Project description:The mammalian epidermis undergoes constant renewal replenished by a pool of stem cells and terminal differentiation of their progeny. This is accompanied by changes in gene expression and morphology orchestrated, in part, by epigenetic modifiers. Here, we defined the role of histone acetyltransferase KAT2A in epidermal homeostasis and provided a comparative analysis that revealed key functional divergence with its paralogue, KAT2B. In contrast to KAT2B's reported function in epidermal differentiation, KAT2A supports the undifferentiated state in keratinocytes. RNA-seq analysis of KAT2A- and KAT2B- depleted keratinocytes revealed dysregulated epidermal differentiation. Depletion of KAT2A led to premature expression of epidermal differentiation genes in the absence of inductive signals, whilst loss of KAT2B delayed differentiation. KAT2A acetyltransferase activity was indispensable in regulating epidermal differentiation gene expression. The metazoan-specific N-terminus of KAT2A was also required to support its function in keratinocytes. We further showed that the interplay between KAT2A- and KAT2B- mediated regulation was important for normal cutaneous wound healing in vivo. Overall, these findings reveal a distinct mechanism in which keratinocytes utilize a pair of highly homologous histone acetyltransferases to support divergent functions in self-renewal and differentiation processes.
2023-06-09 | GSE215244 | GEO
Project description:RNA-seq was conducted to determine differentially expressed genes in whole intestinal epithelial cells between Kat2a/Kat2b DKO and controls.
2023-08-31 | GSE235789 | GEO
Project description:dsRIP-seq was conducted to determine differential enrichment of dsRNA in whole intestinal epithelial cells between Kat2a/Kat2b DKO and controls.
2023-08-31 | GSE235794 | GEO
Project description:Histone acetyltransferases KAT2A and KAT2B are paralogs highly expressed in the intestinal epithelium, but their functions are not well understood. In this study, double knockout of murine Kat2 genes in the intestinal epithelium was lethal, resulting in diminished H3K9ac
expression, loss of stem cells, and robust activation of interferon signaling. Use of pharmacological agents and sterile organoid cultures indicated a cell-intrinsic double-stranded RNA trigger for interferon signaling. Acetyl-proteomics and dsRIP-seq were employed to interrogate the mechanism behind this response, which identified self-derived, mitochondria- encoded double-stranded RNA as the source of intrinsic interferon signaling. KAT2A and KAT2B therefore play an essential role in regulating mitochondrial functions as well as maintaining intestinal health.
2023-07-07 | MSV000092370 | MassIVE
Project description:PArtner and Localizer of BRCA2 (PALB2) is essential to maintain genome stability in human cells. Upon DNA damage by double DNA strand breaks, PALB2 is required to repair DNA by homologous recombination. In undamaged conditions, PALB2 protects coding regions, by preventing DNA stress due to collisions between transcription and replication machineries. PALB2 associates with chromatin, which is essential to fulfill its function in genome stability maintenance, however molecular mechanisms regulating PALB2 chromatin association remain unknown. In our previous published study describing the KAT2A/B(GCN5/PCAF)-acetylome (Fournier et al., Nat.Comm. 2016, doi: 10.1038/ncomms13227) we have identified PALB2 as an acetylated protein target of the acetyltransferases KAT2A (GCN5) and KAT2B (PCAF) in vivo. KAT2A/B-acetylated sites of PALB2 were mapped within its DNA/Chromatin association domain. In this current study, we have conducted in vitro acetyltransferase (AT) assays, by mixing purified recombinant GST-tagged PALB2 full-length (FL) and PALB2 fragment P2.2 which associates with DNA/chromatin (from residues 295-610), with Flag-PCAF, Flag-GCN5 and Flag-GCN5 catalytic mutant (mut), followed by proteomics analysis to map PALB2 acetylated lysines by KAT2A(GCN5) and KAT2B(PCAF) in vitro. PALB2 FL and P2.2 alone, or PALB2 FL and P2.2 mixed with GCN5 catalytic mutant, were used as negative controls.
2023-03-10 | PXD014681 | Pride
Project description:Comprehensive identification of acetylated proteins targeted by the lysine acetyltransferases KAT2A (GCN5) and KAT2B (PCAF), in human cells. KAT2A/B-dependent acetylated proteins were identified by comparing acetylated proteins in whole cell extract of control cells and cells in which KAT2A and KAT2B were simultaneously knocked down. The identification of acetylated proteins was performed using an enrichment-free approach. In order to do so, while facing the challenge of identifying low abundant acetylated peptides within a complex sample mixture, we have screened acetylated peptides starting from a large amount of material, equivalent to 50ug of protein digest (maximum loading capacity of our analytical chromatographic column). By analysing such a large amount of peptides, the level of acetylated peptides was then increased and thus acetylated peptides became easily detectable by mass spectrometry, without the need for enrichment.
2016-12-12 | PXD004669 | Pride
Project description:Transcriptomic changes in primary intestinal epithelium cells with Kat2a/Kat2b DKO.
| PRJNA987626 | ENA
Project description:Enrichment of dsRNA in primary intestinal epithelium cells with Kat2a/Kat2b DKO.
| PRJNA987638 | ENA
Project description:The Endoplasmic Reticulum (ER) unfolded protein response (UPRer) pathway plays an important role for pancreatic β cells to adapt their cellular responses to environmental cues and metabolic stress. Although altered UPRer gene expression appears in rodent and human type 2 diabetic (T2D) islets, the underlying molecular mechanisms remain unknown. We show here that germ-line and β-cell specific disruption of the lysine acetyltransferase 2B (Kat2b) gene in mice leads to impaired insulin secretion and glucose intolerance. Genome wide analysis of Kat2b-regulated genes and functional assays revealed a critical role for KAT2B in maintaining UPRer gene expression and subsequent β-cell function. Importantly, Kat2b expression was decreased in db/db and in human T2D islets and correlated with UPRer genes in normal human islets. In conclusion, KAT2B is a crucial transcriptional regulator for adaptive β-cell function during metabolic stress by controlling UPRer and represents a promising target for T2D prevention and treatment
2016-05-03 | GSE78860 | GEO
Project description:Histone acetyltransferase Kat2a stabilises pluripotency with control of transcriptional heterogeneity
| PRJNA472639 | ENA