HDAC1 and HDAC2 collectively regulate intestinal stem cell homeostasis

Abstract

Histone deacetylases (HDACs) are posttranslational modifiers that deacetylate proteins. Despite their crucial role in numerous biological processes, the use of broad-range HDAC inhibitors (HDACi), has shown clinical efficacy. However, undesired side effects highlight the necessity to better understand the biology of different HDACs and target the relevant HDACs. Using a novel mouse model, in which HDAC1 and HDAC2 can be simultaneously deleted in the intestine of adult mice, we show that the simultaneous deletion of HDAC1 and HDAC2 leads to a rapid loss of intestinal homeostasis. Importantly, this deletion cannot be sustained, and 8 days after initial ablation, stem cells that have escaped HDAC1 or HDAC2 deletion swiftly repopulate the intestinal lining. In vitro ablation of HDAC1 and HDAC2 using intestinal organoid cultures resulted in a down-regulation of multiple intestinal stem cell markers and functional loss of clonogenic capacity. Importantly, treatment of wild-type organoids with class I-specific HDACi MS-275 also induced a similar loss of stemness, providing a possible rationale for the gastrointestinal side effects often observed in HDACi-treated patients. In conclusion, these data show that HDAC1 and HDAC2 have a redundant function and are essential to maintain intestinal homeostasis.-Zimberlin, C. D., Lancini, C., Sno, R., Rosekrans, S. L., McLean, C. M., Vlaming, H., van den Brink, G. R., Bots, M., Medema, J. P., Dannenberg, J.-H. HDAC1 and HDAC2 collectively regulate intestinal stem cell homeostasis. FASEB J. 29, 2070-2080 (2015). www.fasebj.org

Distinct Roles for Intestinal Epithelial Cell‐Specific Hdac1 and Hdac2 in the Regulation of Murine Intestinal Homeostasis

“…b-Naphtoflavone-dependent induction of Hdac1 and Hdac2 deletion in Ah-Cre mice led to intestinal defects, notably eroded epithelium and erased crypts, reduced proliferation, and decreased numbers of both Paneth and goblet cells. Recently, Zimberlin et al (2015) have demonstrated a similar phenotype by deleting both Hdac1 and Hdac2 in the intestinal epithelium in the same Ah-Cre model. This growth inhibitory phenotype was associated with increased g-H2AX foci formation, indicating increased DNA damage responses and the presence of double-strand breaks (Ivashkevich et al, 2012;Redon et al, 2012).…”

Epigenetic Control of Stem Cell Potential during Homeostasis, Aging, and Disease

“…Class I HDACs play a role in differentiation and appear to have a high level of functional redundancy. In intestinal stem cells, simultaneous ablation of Hdac1 and Hdac2 leads to loss of differentiated cells, altered polarization, and increased cell death (Turgeon et al, 2013, Zimberlin et al, 2015). Similar phenotypes occur in the hematopoietic system where the loss of Class I HDACs leads to decreased bone marrow cellularity (Wilting et al, 2010) and in certain instances, loss of stem and progenitor cells (Heideman et al, 2014).…”

Long-Term Culture of Intestinal Cell Progenitors: An Overview of Their Development, Application, and Associated Technologies

“…Reports investigating the role of single components of the diet [51], microbiome [26, 77–81], metabolome [66], immune system [81], and stroma [63, 82] on ICP using ex vivo culture are starting to emerge. These have demonstrated an increased understanding of how the environment elicits cellular and epigenetic alterations [83, 84] that are relevant to human health and intestinal diseases. Beyaz et al, using an ex vivo model, recapitulated ex vivo the environment associated with a high fat diet and established a PPARδ -dependent link to an increase in stemness within the intestinal niche that predisposes to CRC.…”