肝素酶调节染色质可及性。

Heparanase Modulates Chromatin Accessibility.

机构信息

SciLifeLab Uppsala, The Biomedical Center, Department of Medical Biochemistry and Microbiology, University of Uppsala, 75237 Uppsala, Sweden.

Department of Immunology, Genetic and Pathology, University of Uppsala, 75237 Uppsala, Sweden.

出版信息

Cells. 2023 Mar 14;12(6):891. doi: 10.3390/cells12060891.

DOI:10.3390/cells12060891

PMID:36980232

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10047235/

Abstract

Heparanase is the sole endoglucuronidase that degrades heparan sulfate in the cell surface and extracellular matrix (ECM). Several studies have reported the localization of heparanase in the cell nucleus, but the functional role of the nuclear enzyme is still obscure. Subjecting mouse embryonic fibroblasts (MEFs) derived from heparanase knockout (Hpse-KO) mice and applying transposase-accessible chromatin with sequencing (ATAC-seq), we revealed that heparanase is involved in the regulation of chromatin accessibility. Integrating with genome-wide analysis of chromatin states revealed an overall low activity in the enhancer and promoter regions of Hpse-KO MEFs compared with wild-type (WT) MEFs. Western blot analysis of MEFs and tissues derived from Hpse-KO vs. WT mice confirmed reduced expression of H3K27ac (acetylated lysine at N-terminal position 27 of the histone H3 protein). Our results offer a mechanistic explanation for the well-documented attenuation of inflammatory responses and tumor growth in Hpse-KO mice.

摘要

乙酰肝素酶是唯一能够降解细胞表面和细胞外基质（ECM）中硫酸乙酰肝素的内切糖苷酶。有几项研究报道了乙酰肝素酶在细胞核中的定位，但核酶的功能作用仍不清楚。通过对源自乙酰肝素酶敲除（Hpse-KO）小鼠的胚胎成纤维细胞（MEFs）进行处理，并应用转座酶可及染色质测序（ATAC-seq），我们揭示了乙酰肝素酶参与了染色质可及性的调节。与野生型（WT）MEFs 相比，整合对染色质状态的全基因组分析显示，Hpse-KO MEFs 的增强子和启动子区域的整体活性较低。来自 Hpse-KO 与 WT 小鼠的 MEFs 和组织的 Western blot 分析证实了 H3K27ac（组蛋白 H3 蛋白 N 端第 27 位赖氨酸乙酰化）的表达减少。我们的研究结果为 Hpse-KO 小鼠炎症反应和肿瘤生长明显减弱提供了一种机制解释。