Student Name: Felicity Emerson

Student Concentration: Molecular and Cellular Medicine

Committee Member 1: Andrew Grimson

Committee Member 2: Chun Han

Committee Member 3: Paul Soloway

Abstract: Aging is accompanied by a decay of many cellular functions and its reach touches nearly every organelle, including the nucleus. Chromatin structure changes with aging, and evidence from model organisms suggests that proteins that work at chromatin are directly implicated in regulating the aging process. C. elegans is a particularly powerful model with which to interrogate the aging process, as the worm has a short natural lifespan and many well-characterized and highly conserved longevity pathways. Many studies have implicated chromatin factors in longevity in the worm, however the field has been limited by the difficulty of high-resolution chromatin profiling techniques in C. elegans. To this end, we adapted the chromatin profiling technique, CUT&RUN, for use in C. elegans, and optimized the protocol to obtain high-resolution data with limited input material. Subsequently, we used CUT&RUN to interrogate the relationship between two chromatin factors, SET-26 and HCF-1, which our lab previously identified to limit lifespan in C. elegans. We show that SET-26 and HCF-1 operate in the same genetic pathway to modulate lifespan, and we use CUT&RUN to demonstrate that both proteins share overlapping binding profiles at chromatin. Our studies suggest that mechanistically, SET-26, which binds to H3K4me3 via its PHD domain, could function to recruit HCF-1 to chromatin in somatic cells, where the two proteins stabilize each other on a subset of genes. We also identify the histone deacetylase, HDA-1, as an important factor necessary for the extended lifespan of set-26 and hcf-1 mutants, and we show that HDA-1 shares common binding sites with SET-26 and HCF-1 at chromatin. Through gene expression profiling, we see that loss of set-26 and hcf-1 affects gene expression in similar ways, and because loss of hda-1 reverses a subset of these gene expression changes, we hypothesize that HDA-1 antagonizes SET-26 and HCF-1 over control of gene expression, particularly at mitochondrial metabolism genes. As all three chromatin factors are conserved in humans and the relationship between SET-26 and HCF-1 appears to be conserved, our study raises exciting new questions about the function of these proteins and their role in aging in diverse organisms.

Publications: Emerson, Felicity & Chiu, Caitlin & Lin, Laura & Riedel, Christian & Zhu, Ming & Lee, Siu. (2023). The chromatin factors SET-26 and HCF-1 oppose the histone deacetylase HDA-1 in longevity and gene regulation in C. elegans. bioRxiv : the preprint server for biology. 10.1101/2023.03.20.531974. Emerson, Felicity & Lee, Siu. (2022). CUT&RUN for Chromatin Profiling in Caenorhabditis elegans. Current Protocols. 2. 10.1002/cpz1.445. Li, Cheng-Lin & Pu, Mintie & Wang, Wenke & Chaturbedi, Amaresh & Emerson, Felicity & Lee, Siu. (2021). Region-specific H3K9me3 gain in aged somatic tissues in Caenorhabditis elegans. PLOS Genetics. 17. e1009432. 10.1371/journal.pgen.1009432. Church, Jamie & Tijerina, Pamella & Emerson, Felicity & Coburn, Morgan & Blum, Jason & Zelikoff, Judith & Schwartzer, Jared. (2017). Perinatal exposure to concentrated ambient particulates results in autism-like behavioral deficits in adult mice. Neurotoxicology. 65. 10.1016/j.neuro.2017.10.007.