Project Title

Knockdown of the PRC2 complex rescues developmental defects caused by inappropriate inheritance of histone methylation in C. elegans

Presenters

Sydney MorganFollow

Academic department under which the project should be listed

CSM - Molecular and Cellular Biology

Faculty Sponsor Name

Dr. Brandon Carpenter

Disciplines

Developmental Biology | Genomics | Molecular Genetics

Abstract (300 words maximum)

Histone methylation is a post-transcriptional modification to the N-terminal tails of histone core proteins that regulates DNA accessibility, and consequently, gene expression. Like DNA, histone methylation can be inherited between generations, and is highly regulated during embryonic development. At fertilization, histone methylation must undergo maternal reprogramming to reset the epigenetic landscape in the new zygote. During maternal reprogramming of histone methylation in C. elegans, H3K4me (a modification associated with active transcription) is removed by the H3K4 demethylase, SPR-5, and H3K9me (a modification associated with transcriptional repression) is subsequently added by the histone methyltransferase, MET-2. Recently, it was demonstrated that SPR-5; MET-2 maternal reprogramming antagonizes the H3K36 methyltransferase, MES-4, which maintains a transcriptional memory of a subset of germline genes between generations. Maternal loss of SPR-5 and MET-2 results in ectopic expression of MES-4 germline genes in somatic tissues and a severe developmental delay. Work from the Strome Lab showed that the Polycomb Repressive Complex II (PRC2), which includes the H3K27 methyltransferase, MES-2, antagonizes MES-4 to maintain proper gene expression during early embryogenesis. This data hints that in the absence of SPR-5; MET-2 maternal reprogramming, MES-2 may prevent a more severe developmental delay by antagonizing MES-4. To test this hypothesis, we knocked down MES-2 using RNAi and found that the developmental delay in spr-5; met-2 mutants is completely rescued. This exciting result suggests that H3K27me may contribute to MES-4 germline gene misexpression in the somatic tissues of spr-5; met-2 mutants. We are currently performing RNA-seq and ChIP-seq experiments to further examine how these histone modifying enzymes cooperate to regulate proper germline versus somatic gene expression. Our work will provide mechanistic insight into how developmental abnormalities arise in Sotos and Kabuki Syndrome patients suffering from mutations in these same enzymes.

Project Type

Oral Presentation (15-min time slots)

How will this be presented?

Yes, in person

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Knockdown of the PRC2 complex rescues developmental defects caused by inappropriate inheritance of histone methylation in C. elegans

Histone methylation is a post-transcriptional modification to the N-terminal tails of histone core proteins that regulates DNA accessibility, and consequently, gene expression. Like DNA, histone methylation can be inherited between generations, and is highly regulated during embryonic development. At fertilization, histone methylation must undergo maternal reprogramming to reset the epigenetic landscape in the new zygote. During maternal reprogramming of histone methylation in C. elegans, H3K4me (a modification associated with active transcription) is removed by the H3K4 demethylase, SPR-5, and H3K9me (a modification associated with transcriptional repression) is subsequently added by the histone methyltransferase, MET-2. Recently, it was demonstrated that SPR-5; MET-2 maternal reprogramming antagonizes the H3K36 methyltransferase, MES-4, which maintains a transcriptional memory of a subset of germline genes between generations. Maternal loss of SPR-5 and MET-2 results in ectopic expression of MES-4 germline genes in somatic tissues and a severe developmental delay. Work from the Strome Lab showed that the Polycomb Repressive Complex II (PRC2), which includes the H3K27 methyltransferase, MES-2, antagonizes MES-4 to maintain proper gene expression during early embryogenesis. This data hints that in the absence of SPR-5; MET-2 maternal reprogramming, MES-2 may prevent a more severe developmental delay by antagonizing MES-4. To test this hypothesis, we knocked down MES-2 using RNAi and found that the developmental delay in spr-5; met-2 mutants is completely rescued. This exciting result suggests that H3K27me may contribute to MES-4 germline gene misexpression in the somatic tissues of spr-5; met-2 mutants. We are currently performing RNA-seq and ChIP-seq experiments to further examine how these histone modifying enzymes cooperate to regulate proper germline versus somatic gene expression. Our work will provide mechanistic insight into how developmental abnormalities arise in Sotos and Kabuki Syndrome patients suffering from mutations in these same enzymes.

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