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LaminA/C regulates epigenetic and chromatin architecture changes upon aging of hematopoietic stem cells

ABSTRACT: The decline of hematopoietic stem cell (HSC) function upon aging contributes to the senescent immune remodeling and to leukemia pathogenesis. Aged HSCs show changes in their epigenome, like alterations in the global and local DNA/histone methylation and histone acetylation landscape. Previously, we showed a correlation between high Cdc42 activity and the loss of intra-nuclear epigenetic polarity (epipolarity), as indicated by the specific location of histone H4 lysine 16 acetylation (H4K16ac). Here, we show that not all histone modifications display a polar localization and that loss of H4K16ac amount and epipolarity is specific to aged HSCs. Increased levels of H4K16ac are insufficient to restore polarity in aged HSCs and for the restoration of HSC function. Changes in H4K16ac upon aging and rejuvenation of HSCs are correlated to a shift of chromosome 11 architecture and nuclear volume and shape. Surprisingly, by taking advantage of knock-out mouse models we demonstrate that increased Cdc42 activity levels correlate with the repression of LaminA/C expression, which control chromosome 11 distribution, H4K16ac polarity and the nuclear volume and shape of aged HSCs. These chromatin and epigenetic architecture changes are targeted by altering the activity of the small RhoGTPase Cdc42, that regulates LaminA/C. Collectively, our data show that chromatin architecture changes in stem cells are reversible by changing levels of Cdc42 activity, revealing an unanticipated way to pharmacologically target LaminA/C expression and revert alterations of the epigenetic architecture in aged HSCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE119466 | GEO | 2018/09/05

REPOSITORIES: GEO

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Project description:Cdc42 is a key regulator of cell polarity that modulates cytoskeletal dynamics, morphology, and directional movement and plays a important role in maintaining epithelial integrity. Loss of Cdc42 in the small intestine causes disrupted polarity, hyperplasia, and mislocalization and expansion of transit-amplifying (TA) cells at the expense of intestinal stem cells (ISCs). KRAS, on the other hand, is essential for intestinal cell proliferation and differentiation, and oncogenic KRAS mutations can lead to disrupted epithelial homeostasis and contribute to gastrointestinal transformation. A human cancer database analysis suggests that loss of polarity mutations and oncogenic KRAS mutations are mutually exclusive in colon cancer patients. We found that intestinal epithelium-specific deletion of Cdc42 combined with oncogenic Kras expression in inducible Villin-CreER mice causes severe defects in the small intestine leading to lethality. Mice with Cdc42 deletion and oncogenic Kras expression in the intestinal epithelium exhibited reduced weight, disrupted villous mucosal structure, altered tight junction protein expression, reduced proliferation, loss of ISCs, inflammation, and enterocyte necrosis. These defects resemble Necrotizing Enterocolitis (NEC), a severe gastrointestinal disorder affecting preterm infants characterized by inflammation and necrosis of the small intestine epithelial cells. Single cell RNAseq analyses revealed that Cdc42 loss combined with oncogenic Kras expression resulted in disrupted intestinal polarity machinery with altered hippo signaling, exacerbated inflammation highlighted with elevated IL1 expression, and necroptosis. Targeted inhibition of necroptosis, IL-1 receptor, or YAP signaling rescues NEC-like defects. Additionally, ISCs-specific deletion of Cdc42 and oncogenic Kras expression induced by an intestinal stem cell driver, Omlf4-CreER, led to similar NEC-like defects in the mouse intestinal epithelium. These findings present a mechanism involving YAP-IL1-necroptosis signaling by combined disruption of polarity and oncogenic cues such as Kras in intestine function and provide insights into the effects of hyperactivation of these pathways in disrupting intestinal epithelia.