MLL5 is involved in retinal photoreceptor maturation through facilitating CRX-mediated photoreceptor gene transactivation

Xiaoming Zhang; Bo-Wen Zhang; Lue Xiang; Hui Wu; Supit Alva Sahiri Alexander; Peipei Zhou; Melvin Zi-Yu Dai; Xiaoyun Wang; Wenjun Xiong; Yan Zhang; Zi-Bing Jin; Lih-Wen Deng

doi:10.1016/j.isci.2022.104058

MLL5 is involved in retinal photoreceptor maturation through facilitating CRX-mediated photoreceptor gene transactivation

iScience. 2022 Mar 11;25(4):104058. doi: 10.1016/j.isci.2022.104058. eCollection 2022 Apr 15.

Authors

Xiaoming Zhang^{1

2}, Bo-Wen Zhang^{3

4}, Lue Xiang³, Hui Wu¹, Supit Alva Sahiri Alexander⁵, Peipei Zhou⁶, Melvin Zi-Yu Dai¹, Xiaoyun Wang⁷, Wenjun Xiong⁵, Yan Zhang⁸, Zi-Bing Jin⁷, Lih-Wen Deng^{1

9

10

11}

Affiliations

¹ Department of Biochemistry, Yong Loo Lin School of Medicine (YLLSOM), National University of Singapore, Singapore 117597, Singapore.
² NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, National Institutes for Food and Drug Control, Beijing 102629, China.
³ Laboratory for Stem Cell & Retinal Regeneration, Institute of Stem Cell Research, The Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China.
⁴ Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China.
⁵ Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China.
⁶ Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
⁷ Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing 100730, China.
⁸ Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
⁹ National University Cancer Institute, Singapore National University Health System (NUHS), Singapore 119074, Singapore.
¹⁰ NUS Center for Cancer Research, YLLSOM, NUS, Singapore 117599, Singapore.
¹¹ NUS Graduate School - Integrative Sciences and Engineering Programme, NUS, Singapore 119077, Singapore.

Abstract

Histone methylation, particularly at the H3K4 position, is thought to contribute to the specification of photoreceptor cell fate; however, the mechanisms linking histone methylation with transcription factor transactivation and photoreceptor gene expression have not yet been determined. Here, we demonstrate that MLL5 is abundantly expressed in the mouse retina. Mll5 deficiency impaired electroretinogram responses, alongside attenuated expression of a number of retina genes. Mechanistic studies revealed that MLL5 interacts with the retina-specific transcription factor, CRX, contributing to its binding to photoreceptor-specific gene promoters. Moreover, depletion of MLL5 impairs H3K4 methylation and H3K79 methylation, which subsequently compromises CRX-CBP assembly and H3 acetylation on photoreceptor promoters. Our data support a scenario in which recognition of H3K4 methylation by MLL5 is required for photoreceptor-specific gene transcription through maintaining a permissive chromatin state and proper CRX-CBP recruitment at promoter sites.

Keywords: Biological sciences; Molecular biology; Molecular neuroscience; Neuroscience; Omics.