Transcriptional Regulation by ATOH1 and its Target SPDEF in the Intestine

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• 作者：Yuan-Hung Lo¹ ; Eunah Chung² ; ³ ; Zhaohui Li⁴ ; Ying-Wooi Wan⁴ ; Maxime M. Mahe⁵ ; Min-Shan Chen¹ ; Taeko K. Noah⁶ ; Kristin N. Bell⁷ ; Hari Krishna Yalamanchili⁴ ; Tiemo J. Klisch⁸ ; Zhandong Liu⁵ ; Joo-Seop Park² ; ³ ; ^{joo-seop.park@cchmc.org} ; Noah F. Shroyer¹ ; ⁹ ; ^{noah.shroyer@bcm.edu}
• 关键词：ATOH1 ; SPDEF ; Transcription ; Intestinal Epithelium ; Villin-creER ; TRE-Spdef ; Atoh1GFP ; Atoh1Flag
• 刊名：CMGH Cellular and Molecular Gastroenterology and Hepatology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：3
• 期：1
• 页码：51-71
• 全文大小：7736 K
• 卷排序：3

文摘

The transcription factor atonal homolog 1 (ATOH1) controls the fate of intestinal progenitors downstream of the Notch signaling pathway. Intestinal progenitors that escape Notch activation express high levels of ATOH1 and commit to a secretory lineage fate, implicating ATOH1 as a gatekeeper for differentiation of intestinal epithelial cells. Although some transcription factors downstream of ATOH1, such as SPDEF, have been identified to specify differentiation and maturation of specific cell types, the bona fide transcriptional targets of ATOH1 still largely are unknown. Here, we aimed to identify ATOH1 targets and to identify transcription factors that are likely to co-regulate gene expression with ATOH1.MethodsWe used a combination of chromatin immunoprecipitation and messenger RNA–based high-throughput sequencing (ChIP-seq and RNA-seq), together with cell sorting and transgenic mice, to identify direct targets of ATOH1, and establish the epistatic relationship between ATOH1 and SPDEF.ResultsBy using unbiased genome-wide approaches, we identified more than 700 genes as ATOH1 transcriptional targets in adult small intestine and colon. Ontology analysis indicated that ATOH1 directly regulates genes involved in specification and function of secretory cells. De novo motif analysis of ATOH1 targets identified SPDEF as a putative transcriptional co-regulator of ATOH1. Functional epistasis experiments in transgenic mice show that SPDEF amplifies ATOH1-dependent transcription but cannot independently initiate transcription of ATOH1 target genes.ConclusionsThis study unveils the direct targets of ATOH1 in the adult intestines and illuminates the transcriptional events that initiate the specification and function of intestinal secretory lineages.