CAREER: How transgenerational chromatin landscapes shape C. elegans cell fate

The experiences of our ancestors can affect our own biology. Studies in animals and humans have shown that stress or environmental exposure can be epigenetically encoded in genomes and inherited for multiple generations. But it is still not clear how epigenetic inheritance occurs, nor what it might mean for descendants. In cells, genomes are packaged into chromatin, where DNA is wrapped around histone proteins. Modifications are added or removed from histones, controlling how the genome is used for gene expression. The inheritance of chromatin from parent to child is tightly regulated and involves the erasure of most – but crucially, not all – modifications from parental genomes. Because this process is completely essential for development, most animals do not survive errors, making it hard to study. This project harnesses the power of the genetic model C. elegans to ask: How do heritable chromatin landscapes regulate gene expression? What information must be erased, and what must be retained? Data will be generated in a traditional research lab and in course-based undergraduate research experiences that are specifically designed to support first-generation college students. Embedding research into required courses for the biology major resolves challenges that would normally limit participation in undergraduate research, and therefor broadens access to STEM careers (including those in biotechnology or computational biology). Because regulating epigenetic inheritance is so important for survival, it is highly conserved among all eukaryotes. Therefore, discoveries made in C. elegans will identify fundamental aspects of how epigenetic inheritance affects cell fate, and have broader impacts on biotechnology applications like tissue engineering or gene therapy. In this model for transgenerational epigenetic inheritance, C. elegans mutants gradually accumulate repressive chromatin over many generations. A mutation in either WDR-5 (which belongs to the MLL/COMPASS H3K4 methylating complex), or JHDM-1 (a putative demethylase for H3K9me), causes the gradual, genome-wide accumulation of H3K9me2, a modification associated with heterochromatin in C. elegans. This project examines how the inappropriate inheritance of chromatin affects embryonic, larval, and germline development. Aim 1 examines zygotic genome activation and embryonic transcription using fluorescence reporters and RNA-seq. Aim 2 probes embryonic chromosome structure using high-resolution microscopy, ATAC-seq, and CUT&RUN. Aim 3 tests how maternal and paternal chromosomes interact in the embryo when they are burdened with different chromatin landscapes. To integrate these complex genomic and phenotypic datasets, researchers will use artificial intelligence (AI) to develop a machine learning (ML) model that tracks effects across generational time. Importantly, each research aim is fully integrated with Aim 4’s curriculum-wide course-based undergraduate research experience for first-generation college students majoring in biology. This proposal will generate a mechanistic understanding of how heritable histone modifications influence transcription. It will also establish a research paradigm for studying how chromatin landscapes regulate gene expression and cell identity for organismal success. Because the mechanisms of epigenetic reprogramming are highly conserved across all eukaryotes, this study will transform our understanding of how epigenomes shape development and physiology across taxa. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2538853 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT,01003031DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Teresa Lee | Institution: University of Massachusetts Lowell, LOWELL, MA | Award Amount: $880,000 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2538853 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2538853.html