The zinc-finger transcription factor LSL-1 is a major regulator of the germline transcriptional program in Caenorhabditis elegans

Abstract

Specific gene transcriptional programs are required to ensure proper proliferation and differentiation processes underlying the production of specialized cells during development. Gene activity is mainly regulated by the concerted action of transcription factors and chromatin proteins. In the nematode C. elegans, mechanisms that silence improper transcriptional programs in germline and somatic cells have been well studied, however, how are tissue specific sets of genes turned on is less known. LSL-1 is herein defined as a novel crucial transcriptional regulator of germline genes in C. elegans. LSL-1 is first detected in the P4 blastomere and remains present at all stages of germline development, from primordial germ cell proliferation to the end of meiotic prophase. lsl-1 loss-of-function mutants exhibit many defects including meiotic prophase progression delay, a high level of germline apoptosis, and production of almost no functional gametes. Transcriptomic analysis and ChIP-seq data show that LSL-1 binds to promoters and acts as a transcriptional activator of germline genes involved in various processes, including homologous chromosome pairing, recombination, and genome stability. Furthermore, we show that LSL-1 functions by antagonizing the action of the heterochromatin proteins HPL-2/HP1 and LET-418/Mi2 known to be involved in the repression of germline genes in somatic cells. Based on our results, we propose LSL-1 to be a major regulator of the germline transcriptional program during development.

A Transcription Factor Functional Atlas of Germline Development

“…We also identified 128 TFs that control germ cell behavior in the distal germ line, including multiple TFs previously reported. For example, our screen confirmed previous studies identifying a zincfinger TF LSL-1 that limits TZ size, and the heat shock factor HSF-1 and chromatin factor XND-1 that promote germ cell proliferation in the PZ (Edwards et al, 2021;Mainpal et al, 2015;Rodriguez-Crespo et al, 2022). Our secondary screen focused on the TFs important for controlling PZ size to define whether these factors potentially control Notch signaling and/or mitotic cell cycle -two critical determinants of PZ germ cell behavior.…”

“…As transcription is activated early during larval development, TFs likely play important roles in germ cell transitions and cell behavior during larval and adult development. Indeed, previous studies have identified key TFs that regulate germ cell and gamete development (Chi and Reinke, 2006;Curran et al, 2009;Edwards et al, 2021;Rodriguez-Crespo et al, 2022). However, no systematic in vivo assessment of TF function in the C. elegans germ line, or in any organism, has been conducted.…”

Ectopic transcription due to inappropriately inherited histone methylation may interfere with the ongoing function of terminally differentiated cells

“…Therefore, we also tried to shut off the ectopic expression of MES-4 targeted germline genes by performing RNAi against lsl-1. LSL-1 is a germline transcription factor that is actively required for the transcription of many germline expressed genes 17 . We found that knockdown of LSL-1 after the L2 stage in spr-5; met-2 mutants results in an even stronger rescue of the chemotaxis index in spr-5; met-2 mutants from 0.0 to 0.36, such that the chemotaxis index is similar to Wild Type (0.55) under these experimental conditions (Figure 4).…”

“…LSL-1 is first transcribed in P4, continues to be expressed during germline development in all four stages of larval development (L1 to L4), and remains on into the adult. Without, LSL-1 the germline has many defects including defects in meiosis, germline apoptosis and the production of almost no functional gametes 17 .…”

“…This suggests that these complexes may be functioning to reinforce SPR-5/MET-2 maternal reprogramming in somatic tissues. In the germline, the function of NuRD is antagonized by the germline transcription factor LSL-1 17 .…”