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

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.

Roles of extracellular vesicles in the aging microenvironment and age‐related diseases

“…Most genes can also display changes in the epigenome and chromatin organization, typically at senescence-associated heterochromatin foci (SAHF), to drive aging. These changes can be triggered by disruption of mitochondrial function, glucose metabolism and autophagy (Di Micco et al, 2021;Zhang et al, 2021).…”

Interplay Between Glucose Metabolism and Chromatin Modifications in Cancer

“…Our group also showed that the yeast pyruvate kinase Pyk1 can form a complex called SESAME to phosphorylate histone H3T11 (H3pT11) to repress gene expression in response to glucose and serine availability . We also find that SESAME phosphorylates H3T11 at telomeres to maintain the integrity of telomere heterochromatin during chronological aging (Zhang et al, 2021). H3pT11 can contribute to tumorigenesis by recruiting chromatin modifying factors.…”

Phosphorylation of Jhd2 by the Ras-cAMP-PKA(Tpk2) pathway regulates histone modifications and autophagy

“…Total RNA was isolated from exponentially growing yeast cells by standard phenol-chloroform extraction procedures 17 . The extracted RNA was treated with RNase-free DNase I (Takara, 2270 A) and quantified by Nanodrop 2000 (Thermo scientific).…”

“…For example, glucose can be converted to acetyl-CoA, which is then fueled to histone acetyltransferases (HATs) to increase the overall histone acetylation and alter the global chromatin structure 14 , 15 . We have previously reported that glycolysis is required for pyruvate kinase-mediated histone H3 phosphorylation at threonine 11 (H3pT11) 16 , which confers cell resistance to oxidative stress and maintains normal telomere silencing 17 , 18 . Pyruvate kinase-containing SESAME complex interacts with histone acetyltransferase SAS complex to promote histone H4K16ac and maintain transcription silencing at subtelomere regions 19 .…”