CONSEQUENCES OF CHROMATIN MOSAICISM AND PERSISTENCE IN NEURONAL PLASTICITY AND DISEASE

The regulatory information in genomes is not encoded in DNA sequence alone. The chromatin context, how the DNA is packaged and interacts with itself and other factors, enables variation upon the shared genome sequence. This thesis investigates how chromatin heterogeneity contributes to variability in fragile X syndrome (FXS), a neurodevelopmental disorder, cell-type identities, and neuronal plasticity. In FXS, using imaging and genome-wide H3K9me3 profiling in patient-derived neural progenitor cells, I find that the mutation-length CGG expansion on the X chromosome drives inter-chromosomal clustering of heterochromatin domains at Megabase-scale H3K9me3 domains, termed BREACHes. BREACHes form on the X chromosome and autosomes and encompass synaptic genes silenced independently of FMRP loss. Extending to an FXS patient cohort, I show that FXS H3K9me3 BREACHes are mosaic across individuals and among isogenic subclones. The heterogeneity predicts variation in gene repression and identifies genes that when profiled in blood improves prediction of FXS syndrome severity beyond the classic prognosticator, FMRP alone. To further investigate chromatin heterogeneity, I apply FISHnet, a computational algorithm that detects hierarchically nested chromatin folding in imaging data and find that individual chromosome alleles harbor nested domain structures and that boundary positions vary in cell-type-informative architectures. In neuronal plasticity, using human iPSC-derived neurons, I describe how activity-dependent chromatin loops persist for at least five days following stimulation. Chromatin loops plasticity and persistent histone modification at regulatory elements are linked to persistent transcriptional changes and attenuated transcriptional re-induction and protection from homeostatic downscaling upon restimulation. Altogether, these data demonstrate how chromatin heterogeneity reflects meaningful genome regulatory variation that can influence disease expressivity and enable neuronal adaptation to experience.

Author dc:creator

• Pham, Kenneth

Advisor dc:contributor.advisor

• Phillips-Cremins, Jennifer

• Biology

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/62901

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/62901