MBD5 and MBD6 couple DNA methylation to gene silencing through the J-domain protein SILENZIO

Lucia Ichino; Brandon A Boone; Luke Strauskulage; C Jake Harris; Gundeep Kaur; Matthew A Gladstone; Maverick Tan; Suhua Feng; Yasaman Jami-Alahmadi; Sascha H Duttke; James A Wohlschlegel; Xiaodong Cheng; Sy Redding; Steven E Jacobsen

doi:10.1126/science.abg6130

MBD5 and MBD6 couple DNA methylation to gene silencing through the J-domain protein SILENZIO

Science. 2021 Jun 3:eabg6130. doi: 10.1126/science.abg6130. Online ahead of print.

Authors

Lucia Ichino^{1

2}, Brandon A Boone^{1

2}, Luke Strauskulage^{3

4}, C Jake Harris², Gundeep Kaur⁵, Matthew A Gladstone², Maverick Tan², Suhua Feng^{2

6}, Yasaman Jami-Alahmadi⁷, Sascha H Duttke⁸, James A Wohlschlegel⁷, Xiaodong Cheng⁵, Sy Redding³, Steven E Jacobsen^{9

2

6

10}

Affiliations

¹ Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
² Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94143, USA.
⁴ Tetrad Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁶ Eli and Edyth Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁷ Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁸ Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
⁹ Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA. jacobsen@ucla.edu.
¹⁰ Howard Hughes Medical Institute (HHMI), UCLA, Los Angeles, CA 90095, USA.

Abstract

DNA methylation is associated with transcriptional repression of eukaryotic genes and transposons, but the downstream mechanism of gene silencing is largely unknown. Here we describe two Arabidopsis methyl-CpG binding domain proteins, MBD5 and MBD6, that are recruited to chromatin by recognition of CG methylation, and redundantly repress a subset of genes and transposons without affecting DNA methylation levels. These methyl-readers recruit a J-domain protein, SILENZIO, that acts as a transcriptional repressor in loss-of-function and gain-of-function experiments. J-domain proteins often serve as co-chaperones with HSP70s. Indeed, we found that SILENZIO's conserved J-domain motif was required for its interaction with HSP70s and for its silencing function. These results uncover an unprecedented role of a molecular chaperone J-domain protein in gene silencing downstream of DNA methylation.

Abstract

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