Robert, V. J. | bioRxiv Science

bioRxiv2023

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

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.

genetics↗

bioRxiv2019

The C. elegans SET-2 histone methyltransferase maintains germline fate by preventing progressive transcriptomic deregulation across generations

Chromatin factors contribute to germline maintenance by preserving a germline-appropriate transcriptional program. In the absence of the conserved histone H3 Lys4 (H3K4) methyltransferase SET-2, C. elegans germ cells progressively lose their identity over generations, leading to sterility. How this transgenerational loss of fertility results from the absence of SET-2 is unknown. Here we performed expression profiling across generations on germlines from mutant animals lacking SET-2 activity. We found that gene deregulation occurred in 2 steps: a priming step in early generations progressing to loss of fertility in later generations. By performing Within-Class Analysis (WCA), a derivative of Principal Component Analysis, we identified transcriptional signatures associated with SET-2 inactivation, both at the priming step and later on during loss of fertility. Further analysis showed that repression of germline genes, derepression of somatic programs, and X-chromosome desilencing through interference with PRC2-dependent repression, are priming events driving loss of germline identity in the absence of SET-2. Decreasing expression of identified priming genes, including the C/EBP homologue cebp-1 and TGF-{beta} pathway components, was sufficient to delay the onset of sterility, suggesting that they individually contribute to the loss of germ cell fate. Altogether, our findings illustrate how the loss of a chromatin regulator at one generation can progressively deregulate multiple transcriptional and signaling programs, ultimately leading to loss of appropriate cell fate.

genetics↗