The SAM domain-containing protein 1 (SAMD1) acts as a repressive chromatin regulator at unmethylated CpG islands

Sci Adv. 2021 May 12;7(20):eabf2229. doi: 10.1126/sciadv.abf2229.

Bastian Stielow ¹, Yuqiao Zhou ², Yinghua Cao ², Clara Simon ¹, Hans-Martin Pogoda ³ ⁴, Junyi Jiang ², Yanpeng Ren ², Sabrina Keita Phanor ⁵, Iris Rohner ¹, Andrea Nist ⁶, Thorsten Stiewe ⁶, Matthias Hammerschmidt ³ ⁴, Yang Shi ⁷ ⁸, Martha L Bulyk ⁵ ⁹, Zhanxin Wang ¹⁰, Robert Liefke ¹¹ ¹²

Affiliations

1 Institute of Molecular Biology and Tumor Research (IMT), Philipps University of Marburg, 35043 Marburg, Germany.
2 Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, 19 Xinjiekouwai Avenue, Beijing 100875, China.
3 Institute of Zoology, University of Cologne, Cologne, Germany.
4 Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
5 Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
6 Genomics Core Facility, Institute of Molecular Oncology, Member of the German Center for Lung Research (DZL), Philipps University of Marburg, 35043 Marburg, Germany.
7 Division of Newborn Medicine and Epigenetics Program, Department of Pediatrics, Boston Children's Hospital, Boston, Harvard Medical School, Boston, MA 02115, USA.
8 Ludwig Institute for Cancer Research, Oxford University, Oxford, UK.
9 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
10 Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, 19 Xinjiekouwai Avenue, Beijing 100875, China. [email protected] [email protected].
11 Institute of Molecular Biology and Tumor Research (IMT), Philipps University of Marburg, 35043 Marburg, Germany. [email protected] [email protected].
12 Department of Hematology, Oncology and Immunology, University Hospital Giessen and Marburg, 35043 Marburg, Germany.

PMID: 33980486 DOI: 10.1126/sciadv.abf2229

Abstract

CpG islands (CGIs) are key regulatory DNA elements at most promoters, but how they influence the chromatin status and transcription remains elusive. Here, we identify and characterize SAMD1 (SAM domain-containing protein 1) as an unmethylated CGI-binding protein. SAMD1 has an atypical winged-helix domain that directly recognizes unmethylated CpG-containing DNA via simultaneous interactions with both the major and the minor groove. The SAM domain interacts with L3MBTL3, but it can also homopolymerize into a closed pentameric ring. At a genome-wide level, SAMD1 localizes to H3K4me3-decorated CGIs, where it acts as a repressor. SAMD1 tethers L3MBTL3 to chromatin and interacts with the KDM1A Histone Demethylase complex to modulate H3K4me2 and H3K4me3 levels at CGIs, thereby providing a mechanism for SAMD1-mediated transcriptional repression. The absence of SAMD1 impairs ES cell differentiation processes, leading to misregulation of key biological pathways. Together, our work establishes SAMD1 as a newly identified chromatin regulator acting at unmethylated CGIs.

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