Epigenetics seminars

This lecture examines how genetic predisposition interacts with environmental exposure in disease. It reviews methods for detecting these interactions, the role of large biobanks and examples including obesity. Gene regulation and environmentally influenced epigenetic changes provide possible molecular mechanisms.

Anne Ferguson-Smith examines the layer of epigenetic information that influences how the DNA sequence is used. Research on this layer has changed understanding of genome function, responses to the environment and possible inheritance beyond DNA sequence alone. The lecture considers how epigenetics affects genes and contributes to modern medicine, while asking which widely held claims are supported by evidence and which deserve renewed scrutiny.

One of the most prominent features of the human brain is the fabulous size of the cerebral cortex and its intricate folding, both of which emerge during development. Over the last few years, work from my lab has shown that specific cellular and genetic mechanisms play central roles in cortex folding, particularly linked to neural stem and progenitor cells. Key mechanisms include high rates of neurogenesis, high abundance of basal Radial Glia Cells (bRGCs), and neuron migration, all of which are intertwined during development. We have also shown that primary cortical folds follow highly stereotyped patterns, defined by a spatial-temporal protomap of gene expression within germinal layers of the developing cortex. I will present recent findings from my laboratory revealing novel cellular and genetic mechanisms that regulate cortex expansion and folding. We have uncovered the contribution of epigenetic regulation to the establishment of the cortex folding protomap, modulating the expression levels of key transcription factors that control progenitor cell proliferation and cortex folding. At the single cell level, we have identified an unprecedented diversity of cortical progenitor cell classes in the ferret and human embryonic cortex. These are differentially enriched in gyrus versus sulcus regions and establish parallel cell lineages, not observed in mouse. Our findings show that genetic and epigenetic mechanisms in gyrencephalic species diversify cortical progenitor cell types and implement parallel cell linages, driving the expansion of neurogenesis and patterning cerebral cortex folds.

Self-organization is a universal concept spanning numerous disciplines including mathematics, physics and biology. Chromosomes are self-organizing polymers that fold into orderly, hierarchical and yet dynamic structures. In the past decade, advances in experimental biology have provided a means to reveal information about chromosome connectivity, allowing us to directly use this information from experiments to generate 3D models of individual genes, chromosomes and even genomes. In this talk I will present a novel data-driven modeling approach and discuss a number of possibilities that this method holds. I will discuss a detailed study of the time-evolution of X chromosome inactivation, highlighting both global and local properties of chromosomes that result in topology-driven dynamical arrest and present and characterize a novel type of motion we discovered in knots that may have applications to nanoscale materials and machines.

Understanding how different epigenetic layers are coordinated to facilitate robust lineage decisions during development is one of the fundamental questions in regulatory genomics. Using single-cell epigenomics coupled with cell-type specific high-throughput mapping of enhancer activity, DNA methylation and the 3D genome landscape in vivo, we dissected how the epigenome is rewired during cortical development. We identified and functionally validated key transcription factors such as Neurog2 which underlie regulatory dynamics and coordinate rewiring across multiple epigenetic layers to ensure robust lineage specification. This work showcases the power of high-throughput integrative genomics to dissect the molecular rules of cell fate decisions in the brain and more broadly, how to apply them to evolution and disease.