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Principal Investigator: Lars Benner
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $48,974
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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.
Terms: <21+ years old><AD dementia><Address><Adult><Adult Human><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Amino Acid Motifs><Amino Acid Sequence><Animals><Basal Transcription Factor><Basal transcription factor genes><Binding><Binding Proteins><Binding Sites><Biogenesis><Brachydanio rerio><C elegans><C. elegans><C.elegans><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Caenorhabditis elegans><Cancers><Cannot achieve a pregnancy><Cas nuclease technology><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Combining Site><Complement><Complement Proteins><Complex><DNA Binding><DNA Binding Interaction><DNA Transposable Elements><DNA bound><DNA-Binding Proteins><Danio rerio><Data><Difficulty conceiving><Disease><Disorder><Drosophila melanogaster><Exhibits><Exonuclease><Family><Fecundability><Fecundity><Female><Fertility><Fertility Disorders><Flies><Gametes><Gene Targeting><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic Transcription><Genome Instability><Genomic Instability><Genomics><Germ Cells><Germ Lines><Germ-Line Cells><Global Change><Human><Hybrids><Infertility><Knowledge><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Low Molecular Weight Nuclear RNA><Male Infertility><Malignant Neoplasms><Malignant Tumor><Mammalia><Mammals><Mediating><Mice><Mice Mammals><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Nematoda><Nematodes><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Non-Polyadenylated RNA><Organism><Origin of Life><Ortholog><Orthologous Gene><Pathway interactions><Peptide Domain><Play><Primary Protein Structure><Primary Senile Degenerative Dementia><Protein Binding><Protein Domains><Protein Family><Protein Motifs><Proteins><RNA><RNA Expression><RNA Gene Products><RNA Seq><RNA Splicing><RNA sequencing><RNAseq><Reactive Site><Reagent><Repression><Reproductive Cells><Ribonucleic Acid><Role><Sex Cell><Small Molecular Weight RNA><Small Nuclear RNA><Small RNA><Specific qualifier value><Specificity><Specified><Spliceosomes><Splicing><Sterility><Tertiary Protein Structure><Testicles><Testis><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transposable Elements><Work><Zebra Danio><Zebra Fish><Zebrafish><adulthood><bound protein><complementation><experiment><experimental research><experimental study><experiments><fertility cessation><fertility defect><fertility loss><fly><gene locus><genetic locus><genome integrity><genomic integrity><genomic location><genomic locus><infertile><initial cell><insight><living system><male><malignancy><model organism><mutant><neoplasm/cancer><neuronal><offspring><paralog><paralogous gene><pathway><piRNA><piwi RNA><preservation><primary degenerative dementia><protein complex><protein sequence><recruit><roundworm><senile dementia of the Alzheimer type><sex><sex dimorphism><sexual cell><sexual dimorphism><sexually dimorphic><snRNA><social role><sterile><transcription factor><transcriptome sequencing><transcriptomic sequencing><uRNA>