Abstract
Lgr5+ stem cells are crucial to gut epithelium homeostasis; however, how these cells are maintained is not fully understood. Zinc finger HIT-type containing 1 (Znhit1) is an evolutionarily conserved subunit of the SRCAP chromosome remodeling complex. Currently, the function of Znhit1 in vivo and its working mechanism in the SRCAP complex are unknown. Here we show that deletion of Znhit1 in intestinal epithelium depletes Lgr5+ stem cells thus disrupts intestinal homeostasis postnatal establishment and maintenance. Mechanistically, Znhit1 incorporates histone variant H2A.Z into TSS region of genes involved in Lgr5+ stem cell fate determination, including Lgr5, Tgfb1 and Tgfbr2, for subsequent transcriptional regulation. Importantly, Znhit1 promotes the interaction between H2A.Z and YL1 (H2A.Z chaperone) by controlling YL1 phosphorylation. These results demonstrate that Znhit1/H2A.Z is essential for Lgr5+ stem cell maintenance and intestinal homeostasis. Our findings identified a dominant role of Znhit1/H2A.Z in controlling mammalian organ development and tissue homeostasis in vivo.
Highlights
Lgr5+ stem cells are crucial to gut epithelium homeostasis; how these cells are maintained is not fully understood
We show that Znhit[1] supports Lgr5+ intestinal stem cells (ISCs) through regulating the expression of Lgr[5], Tgfb[1], and Tgfbr[2], which are critical genes involved in Lgr5+ ISC fate determination
Our findings establish the essential role of Zinc finger HIT-type containing 1 (Znhit1)/H2A.Z in controlling Lgr5+ ISC maintenance and intestinal homeostasis, which implicates a therapeutic target in the intervention of gastrointestinal epithelium-related diseases
Summary
Lgr5+ stem cells are crucial to gut epithelium homeostasis; how these cells are maintained is not fully understood. This structural change can be brought by the replacement of canonical histone H2A with histone variant H2A.Z, which leads to chromatin remodeling and subsequent gene expression changes[26,27,28,29,30] It is currently unknown about the incorporation or function of H2A.Z in mammalian organogenesis and tissue homeostasis. As the genetic loss of function mutant mouse for Znhit[1] is currently unavailable, the in vivo role of Znhit[1] in development and tissue homeostasis is completely unknown It is unclear about the mechanism(s) of how Znhit[1] and YL1 act in SRCAP complex to influence H2A.Z incorporation. Our findings establish the essential role of Znhit1/H2A.Z in controlling Lgr5+ ISC maintenance and intestinal homeostasis, which implicates a therapeutic target in the intervention of gastrointestinal epithelium-related diseases
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