SIN3 acts in distinct complexes to regulate the germline transcriptional program inC. elegans

Abstract

The SIN3 transcriptional coregulator influences gene expression through multiple interactions that include histone deacetylases (HDACs). Haploinsufficiency and mutations in SIN3 are the underlying cause of Witteveen-Kolk syndrome and related intellectual disability (ID)/autism syndromes, emphasizing its key role in development. However, little is known about the diversity of its interactions and functions in developmental processes. Here we show that loss of SIN-3, the single SIN3 homologue in Caenorhabditis elegans, results in maternal effect sterility associated with deregulation of the germline transcriptome, including desilencing of X-linked genes. We identify at least two distinct SIN3 complexes containing specific HDACs, and show that they differentially contribute to fertility. Single cell smFISH reveals that in sin-3 mutants, the X chromosome becomes re-expressed prematurely and in a stochastic manner in individual germ cells. Furthermore, we identify histone residues whose acetylation increases in the absence of SIN3. Together, this work provides a powerful framework for the in vivo study of SIN3 and associated proteins.

SIN-3 transcriptional coregulator maintains mitochondrial homeostasis and polyamine flux

“…Together, our analyses suggest that loss of sin-3 perturbs the coordinated expression of mitochondrial genes encoded by nuclear and mitochondrial genomes, possibly resulting in mito-nuclear imbalance and affecting mitochondrial homeostasis. Consistent with mitochondrial dysfunction, sin-3 mutants show reduced fertility, increased sensitivity to oxidative stress, and altered lifespan (Beurton et al, 2019;Caron et al, 2023;Pandey et al, 2018;Sharma et al, 2018), as observed in other mitochondrial mutants (Kropp et al, 2021).…”

“…Previous transcriptomic profiling of animals carrying the sin-3(tm1276) partial loss-of-function allele revealed deregulation of the germline transcriptome, including metabolic genes (Caron et al, 2023). In order to identify high confidence genes regulated by SIN-3, we extended our analysis to genes commonly misregulated in sin-3(tm1276) and sin-3(syb2172) mutant animals that carry a complete loss of function allele obtained by CRISPR-Cas9 (Caron et al, 2023), generating a list of 892 genes (Table S1). Using Worm Cat (Holdorf et al, 2020), within this set we identified a common class of genes with functions related to mitochondria (Figure 1A and Table 1).…”

“…To further examine and quantify changes in mitochondrial morphology in live animals, we used a transgenic strain expressing a red fluorescent protein (RFP) fused at the N terminus to the TOMM-20 translocase of the outer mitochondrial membrane and expressed under the control of a promoter in muscle cells (myo-3p::20Nter::wrmScarlet) (Roy et al, 2022), where mitochondria are abundant and easily visible. We used tm1276 mutant animals because although less fertile than wildtype, they can be maintained as homozygotes, while syb2172 animals are fully sterile (Caron et al, 2023). In wildtype, the majority of body-wall muscle cells have longitudinally arrayed tubular mitochondria, while a smaller percentage show either elongated mitochondria in an interconnected mesh-like network or fragmented mitochondria (Figure 3A).…”

Functional study of chromatin factors uncovers strong lineage determining roles and divergent behaviours between normal and malignant haematopoiesis

“…It is commonly found and stably expressed in mammalian tissues and cells 41 . 41,158,159 . This complex has two variants: (left) the large Rpd3 (Rpd3L) and (right) the small Rpd3 (Rpd3s).…”

“…Figure 5. Structure and function of the Sin3a complex in mammals41,158,159 . This complex has two variants: (left) the large Rpd3 (Rpd3L) and (right) the small Rpd3 (Rpd3s).…”