Dual function of PHF16 in reinstating homeostasis of murine intestinal epithelium after crypt regeneration,Developmental Cell

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Dual function of PHF16 in reinstating homeostasis of murine intestinal epithelium after crypt regeneration
Developmental Cell ( IF 10.7 ) Pub Date : 2024-09-03 , DOI: 10.1016/j.devcel.2024.08.009
Jun-Yeong Ahn ₁ , Somi Kim ₂ , Chang Rok Kim ₁ , Ji-Hyun Lee ₃ , Jong Min Kim ₁ , Thomas M Klompstra ₃ , Yoon Ha Choi ₂ , Yoon Jeon ₄ , Yongwoo Na ₅ , Jong-Seo Kim ₆ , Yuki Okada ₇ , Ho Lee ₄ , Ik Soo Kim ₈ , Jong Kyoung Kim ₉ , Bon-Kyoung Koo ₁₀ , Sung Hee Baek ₁

Affiliation

Creative Research Initiatives Center for Epigenetic Code and Diseases, Seoul National University, Seoul 08826, South Korea; School of Biological Sciences, Seoul National University, Seoul 08826, South Korea.
Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, South Korea.
Center for Genome Engineering, Institute for Basic Science, 55, Expo-ro, Yuseong-gu, Daejeon 34126, South Korea.
Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, South Korea.
School of Biological Sciences, Seoul National University, Seoul 08826, South Korea.
School of Biological Sciences, Seoul National University, Seoul 08826, South Korea; Center for RNA Research, Institute for Basic Science, School of Biological Sciences, Seoul National University, Seoul 08826, South Korea.
Laboratory of Pathology and Development, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
Department of Microbiology, Gachon University College of Medicine, Incheon 21999, South Korea.
Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, South Korea; Institute for Convergence Research and Education in Advanced Technology, Yonsei University, Seoul 03722, South Korea.
Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, South Korea; Center for Genome Engineering, Institute for Basic Science, 55, Expo-ro, Yuseong-gu, Daejeon 34126, South Korea.

Intestinal stem cells (ISCs) are highly vulnerable to damage, being in a constant state of proliferation. Reserve stem cells repair the intestinal epithelium following damage-induced ablation of ISCs. Here, we report that the epigenetic regulator plant homology domain (PHD) finger protein 16 (PHF16) restores homeostasis of the intestinal epithelium after initial damage-induced repair. In Phf16^−/Y mice, revival stem cells (revSCs) showed defects in exiting the regenerative state, and intestinal crypt regeneration failed even though revSCs were still induced in response to tissue damage, as observed by single-cell RNA sequencing (scRNA-seq). Analysis of Phf16^−/Y intestinal organoids by RNA sequencing (RNA-seq) and ATAC sequencing identified that PHF16 restores homeostasis of the intestinal epithelium by inducing retinoic acid receptor (RAR)/retinoic X receptor (RXR) target genes through HBO1-mediated histone H3K14 acetylation, while at the same time counteracting YAP/TAZ activity by ubiquitination of CDC73. Together, our findings demonstrate the importance of timely suppression of regenerative activity by PHF16 for the restoration of gut homeostasis after acute tissue injury.

中文翻译：

PHF16 在隐窝再生后恢复小鼠肠上皮稳态中的双重功能

肠道干细胞（ISC）极易受损，处于持续增殖状态。储备干细胞在损伤诱导的 ISC 消融后修复肠上皮。在这里，我们报道了表观遗传调节因子植物同源结构域（PHD）指蛋白 16 （PHF16）在初始损伤诱导修复后恢复肠上皮的稳态。在 Phf16^−/Y 小鼠中，存活干细胞（revSCs）在退出再生状态时表现出缺陷，并且肠隐窝再生失败，即使 revSCs 仍响应组织损伤而被诱导，如单细胞 RNA 测序（scRNA-seq）所观察到的那样。通过 RNA 测序（RNA-seq）和 ATAC 测序对 Phf16^−/Y 肠道类器官的分析发现，PHF16 通过 HBO1 介导的组蛋白 H3K14 乙酰化诱导视黄酸受体（RAR）/视黄酸 X 受体（RXR）靶基因，从而恢复肠上皮的稳态，同时通过 CDC73 的泛素化抵消 YAP/TAZ 活性。总之，我们的研究结果表明 PHF16 及时抑制再生活性对于急性组织损伤后肠道稳态恢复的重要性。

更新日期：2024-09-03

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