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The molecular characterization of sex-specific piRNA transcription and snRNA transcription in C. elegans

线虫性别特异性 piRNA 转录和 snRNA 转录的分子特征

基本信息

批准号：
10464652
负责人：
Lars Benner
金额：
$ 4.68万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10464652
关键词：
Address Adult Aging Alzheimer&apos s Disease Amino Acid Motifs Amino Acid Sequence Animal Model Animals Binding Binding Proteins Binding Sites Biogenesis CRISPR/Cas technology Caenorhabditis elegans Complement Complex DNA Binding DNA Transposable Elements DNA-Binding Proteins Data Disease Drosophila melanogaster Exhibits Exonuclease Family Female Fertility Fertility Disorders Gene Targeting Genetic Transcription Genomic Instability Genomics Germ Cells Global Change Human Hybrids Infertility Knowledge Link Male Infertility Malignant Neoplasms Mammals Mediating Molecular Mus Nematoda Neurons Organism Orthologous Gene Pathway interactions Play Protein Family Proteins RNA RNA Interference RNA Splicing Reagent Role Small Nuclear RNA Small RNA Specific qualifier value Specificity Spliceosomes Sterility Tertiary Protein Structure Testis Work Zebrafish base experimental study fly genome integrity genomic RNA genomic locus insight male mutant offspring paralogous gene preservation protein complex recruit sex sexual dimorphism transcription factor transcriptome sequencing

项目摘要

Project Summary The molecular characterization of sex-specific piRNA transcription and snRNA transcription in C. elegans. PIWI-interacting RNAs (piRNAs) play key roles in repressing transposons in the germline. Loss of transposon- targeting piRNAs can have sex-specific consequences leading to genomic instability and infertility. However, the mechanisms of sex-specific piRNA expression remain largely unknown. Recent studies have revealed that SNPC-4, a core factor required for snRNA transcription, is also essential for piRNA transcription in C. elegans and suggests that the snRNA transcriptional machinery may have been co-opted to transcribe piRNAs. Therefore, identifying the transcription factors and characterizing the specific protein domains that dictate sex- specific piRNA and snRNA transcriptional specificity will address this critical knowledge gap. The small nuclear RNA activating protein complex (SNAPc) is a conserved heterotrimeric complex consisting of SNAPC1, SNAPC3, and SNAPC4 that facilitates snRNA transcription in mammals. Unlike mammals, C. elegans have several orthologs of SNAPC1 that have sexually dimorphic roles in piRNA biogenesis. My preliminary data show that SNPC-1.2 promotes female piRNA transcription while SNPC-1.3 is a known male piRNA transcription factor. Furthermore, my initial data show the C. elegans SNAPC3 ortholog, SNPC-3.4, facilitates snRNA biogenesis, while SNPC-3.1 and SNPC-3.2 act redundantly to drive both male and female piRNA expression. I will investigate my hypothesis that SNPC-1.2 is a bona fide female piRNA transcription factor and harbors unique protein motifs conferring female piRNA expression, while distinct domains in SNPC-1.3 specify male piRNA expression (Aim 1). Additionally, I predict SNPC-3.4 is a snRNA biogenesis factor, while SNPC-3.1 and SNPC-3.2 act redundantly to drive piRNA transcription. Analogous to the SNPC1 family, I predict that distinct domains within SNPC-3.4 and SNPC-3.1/3.2 specify their recruitment and transcription at snRNA and piRNA genomic loci, respectively (Aim 2). Collectively, these data will elucidate the snRNA and female and male piRNA transcriptional complexes and identify the protein motifs that engender snRNA and sex-specific piRNA transcription. This work may have implications in treating fertility defects that are due to abnormal piRNA expression as well as different neuronal diseases associated with snRNA misregulation such as ALS.

项目总结