Spatiotemporal role of SETD2-H3K36me3 in murine pancreatic organogenesis.

Ping Lu, Junyi Xu, Xuqing Shen, Jiajun Sun, Mingzhu Liu, Ningning Niu, Qidi Wang, Jing Xue

Cell reports 2024 Feb 27

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Pancreas development is tightly controlled by multilayer mechanisms. Despite years of effort, large gaps remain in understanding how histone modifications coordinate pancreas development. SETD2, a predominant histone methyltransferase of H3K36me3, plays a key role in embryonic stem cell differentiation, whose role in organogenesis remains elusive. Here, by combination of cleavage under targets and tagmentation (CUT&Tag), assay for transposase-accessible chromatin using sequencing (ATAC-seq), and bulk RNA sequencing, we show a dramatic increase in the H3K36me3 level from the secondary transition phase and decipher the related transcriptional alteration. Using single-cell RNA sequencing, we define that pancreatic deletion of Setd2 results in abnormalities in both exocrine and endocrine lineages: hyperproliferative tip progenitor cells lead to abnormal differentiation; Ngn3+ endocrine progenitors decline due to the downregulation of Nkx2.2, leading to insufficient endocrine development. Thus, these data identify SETD2 as a crucial player in embryonic pancreas development, providing a clue to understanding the dysregulation of histone modifications in pancreatic disorders. Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Ping Lu, Junyi Xu, Xuqing Shen, Jiajun Sun, Mingzhu Liu, Ningning Niu, Qidi Wang, Jing Xue. Spatiotemporal role of SETD2-H3K36me3 in murine pancreatic organogenesis. Cell reports. 2024 Feb 27;43(2):113703