Metabolic regulation of telomere silencing by SESAME complex-catalyzed H3T11 phosphorylation

Shihao Zhang,Xiangyan Xue,Yuan Zhang,Xilan Yu,Madelaine Gogol,Shanshan Li,Jerry L Workman,Zitong Zha,Qi Yu

doi:10.1038/s41467-020-20711-1

Shihao Zhang, Xiangyan Xue + Show 7 more

Open Access

https://doi.org/10.1038/s41467-020-20711-1

Copy DOI

Abstract

Telomeres are organized into a heterochromatin structure and maintenance of silent heterochromatin is required for chromosome stability. How telomere heterochromatin is dynamically regulated in response to stimuli remains unknown. Pyruvate kinase Pyk1 forms a complex named SESAME (Serine-responsive SAM-containing Metabolic Enzyme complex) to regulate gene expression by phosphorylating histone H3T11 (H3pT11). Here, we identify a function of SESAME in regulating telomere heterochromatin structure. SESAME phosphorylates H3T11 at telomeres, which maintains SIR (silent information regulator) complex occupancy at telomeres and protects Sir2 from degradation by autophagy. Moreover, SESAME-catalyzed H3pT11 directly represses autophagy-related gene expression to further prevent autophagy-mediated Sir2 degradation. By promoting H3pT11, serine increases Sir2 protein levels and enhances telomere silencing. Loss of H3pT11 leads to reduced Sir2 and compromised telomere silencing during chronological aging. Together, our study provides insights into dynamic regulation of silent heterochromatin by histone modifications and autophagy in response to cell metabolism and aging.

Highlights

Telomeres are organized into a heterochromatin structure and maintenance of silent heterochromatin is required for chromosome stability
To determine the genome-wide localization of H3T11 phosphorylation (H3pT11), we performed chromatin immunoprecipitation followed by highthroughput sequencing (ChIP-seq) of H3pT11 in yeast cells grown in glucose-containing rich media and compared it with the positions of H3K4me[3], a histone marker associated with active gene transcription
To test if Serine-responsive SAM-containing Metabolic Enzyme (SESAME)-catalyzed H3pT11 was causally linked to the transcriptional repression of ATG genes, we examined whether SESAME phosphorylates H3T11 at autophagy genes

Summary

Introduction

Telomeres are organized into a heterochromatin structure and maintenance of silent heterochromatin is required for chromosome stability. SESAME phosphorylates H3T11 at telomeres, which maintains SIR (silent information regulator) complex occupancy at telomeres and protects Sir[2] from degradation by autophagy. Our study provides insights into dynamic regulation of silent heterochromatin by histone modifications and autophagy in response to cell metabolism and aging. Sir3/Sir4) and their spread along chromatin in a stepwise manner[11,12,13] During this process, Sir[4] is recruited by Rap[1] and the yeast Ku complex to cis-acting silencer elements[14,15]. The cycles of Sir2-mediated H4K16 deacetylation and Sir[3] recruitment allow the formation of SIR complex and its propagation along the telomere regions, which shields the telomere-proximal DNA from the transcription machinery, leading to transcription repression[4,11,18]. In addition to H4K16ac, Dot1-catalyzed H3K79me[3] and Set1-

Methods

Results

Conclusion