The histone methyltransferase Setd7 promotes pancreatic progenitor identity

Abstract

Cell fate specification depends on transcriptional activation driven by lineage-specific transcription factors as well as changes in chromatin organization. To date, the interplay between transcription factors and chromatin modifiers during development is not well understood. We focus here on the initiation of the pancreatic program from multipotent endodermal progenitors. Transcription factors that play key roles in regulating pancreatic progenitor state have been identified, but the chromatin regulators that help to establish and maintain pancreatic fate are less well known. Using a comparative approach, we identify a crucial role for the histone methyltransferase Setd7 in establishing pancreatic cell identity. We show that Setd7 is expressed in the prospective pancreatic endoderm of Xenopus and mouse embryos prior to Pdx1 induction. Importantly, we demonstrate that setd7 is sufficient and required for pancreatic cell fate specification in Xenopus. Functional and biochemical approaches in Xenopus and mouse endoderm support that Setd7 modulates methylation marks at pancreatic regulatory regions, possibly through interaction with the transcription factor Foxa2. Together, these results demonstrate that Setd7 acts as a central component of the transcription complex initiating the pancreatic program.

Regulation of SETD7 Methyltransferase by SENP3 Is Crucial for Sarcomere Organization and Cachexia

“…However, the same study also detected recruitment of SETD7 independent of MyoD1. Moreover, in pancreatic progenitor cells, SETD7 interaction with Foxa2 was assumed to be a possible mechanism for SETD7 chromatin recruitment (Kofent et al, 2016). The following common themes arose in these studies: (1) how SETD7 is recruited to chromatin is not clearly understood, and (2) indications of other mechanisms responsible for SETD7 recruitment to specific genes.…”

SETD7 Drives Cardiac Lineage Commitment through Stage-Specific Transcriptional Activation

“…Thus previous studies have largely focused on the role of SETD7 on non-histone proteins such as p53 (Chuikov et al, 2004), TAF10 (Kouskouti et al, 2004), DNMT1 (Estève et al, 2009), ERα (Subramanian et al, 2008), E2F1 (Kontaki and Talianidis, 2010), SOX2 (Fang et al, 2014), YAP (Oudhoff et al, 2013), LIN28A (Kim et al, 2014), and HIF1-alpha (Kim et al, 2016). Only a handful of studies showed SETD7 can bind on the promoter regions and regulate individual gene expression (Chen et al, 2012; Kofent et al, 2016). Although these data suggest SETD7 is directly involved in gene transcription, the question of whether SETD7-mediated H3K4me1 is essential for the transcriptional regulation of its target gene remains controversial.…”

Protein Methyltransferase Inhibition Decreases Endocrine Specification Through the Upregulation of Aldh1b1 Expression

“…Histone methylation and acetylation are key epigenetic mechanisms that regulate gene activity and coordinated changes in their patterns are associated with cell fate decisions and stabilization of the differentiated cell state. Specifically, during pancreas development, histone acetyltransferases and methyltransferases have a modulatory role in the early binary cell fate decision between liver and pancreas fates during mouse development and Setd7 was shown to be necessary and sufficient for the specification of pancreatic endoderm in Xenopus . During subsequent pancreas development H3K27me3 patterns change during the differentiation of pancreas progenitors into endocrine progenitors and eventually β‐cells .…”