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Gene expression profiles of CBPWTp53-floxed, CBPAAp53-floxed,CBPWTp53ΔIEC and CBPAAp53ΔIEC intestinal cyrpts

ABSTRACT: CREB-binding protein (CBP) is a coactivator modulating DNA accessibility for transcription factors.CBP phosphorylation at Ser1382/1386 enhanced NF- B- while suppressed p53-mediated gene expression to promote cell growth, suggesting that post-translational modification of CBP regulates cell fate. Here we report that CBP knock-in mice (CBPAA), in which Ser1383/1387 are replaced with alanines, develop a phenotype resembling ulcerative colitis (UC) driven by non-hematopoietic cells. These mice exhibit reduced organoid formation, intestinal epithelial cell (IEC) proliferation, accompanied by increased CBP/p53 binding. All findings are reversed in CBPAA mice with IEC-specific p53 deletion (CBPAAp53ΔIEC) mice. To investigate how impaired CBP phosphorylation results in dampened IEC stemness, RNA-seq was performed to profile the transcriptome of colonic crypt.

ORGANISM(S): Mus musculus

PROVIDER: GSE295556 | GEO | 2026/03/05

REPOSITORIES: GEO

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Project description:Histone deacetylases (Hdac) remove acetyl groups from proteins, influencing global and specific gene expression. Hdacs control inflammation, as shown by Hdac inhibitor-dependent protection from DSS-induced murine colitis. While tissue-specific Hdac knockouts show redundant and specific functions, little is known of their intestinal epithelial cell (IEC) role. We have shown previously that dual Hdac1/Hdac2 IEC-specific loss disrupts cell proliferation and determination, with decreased secretory cell numbers and altered barrier function. We thus investigated how compound Hdac1/Hdac2 or Hdac2 IEC-specific deficiency alters the inflammatory response. Floxed Hdac1 and Hdac2 and villin-Cre mice were interbred. Compound Hdac1/Hdac2 IEC-deficient mice showed chronic basal inflammation, with increased basal Disease Activity Index (DAI) and deregulated Reg gene colonic expression. DSS-treated dual Hdac1/Hdac2 IEC-deficient mice displayed increased DAI, histological score, intestinal permeability and inflammatory gene expression. In contrast to double knockouts, Hdac2 IEC-specific loss did not affect IEC determination and growth, nor result in chronic inflammation. However, Hdac2 disruption protected against DSS colitis, as shown by decreased DAI, intestinal permeability and caspase-3 cleavage. Hdac2 IEC-specific deficient mice displayed increased expression of IEC gene subsets, such as colonic antimicrobial Reg3b and Reg3g mRNAs, and decreased expression of immune cell function-related genes. Our data show that Hdac1 and Hdac2 are essential IEC homeostasis regulators. IEC-specific Hdac1 and Hdac2 may act as epigenetic sensors and transmitters of environmental cues and regulate IEC-mediated mucosal homeostatic and inflammatory responses. Different levels of IEC Hdac activity may lead to positive or negative outcomes on intestinal homeostasis during inflammation Total RNAs from the colon of three control and three Hdac2 IEC-specific knockout mice were isolated with the Rneasy kit (Qiagen, Mississauga, ON, Canada).

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Gene expression profiles of CBPWTp53-floxed, CBPAAp53-floxed,CBPWTp53ΔIEC and CBPAAp53ΔIEC intestinal cyrpts

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