Jordan Hall A308
The instructions to generate the human brain are encoded in the regulatory landscape of our genome. Regulatory DNA sequences primarily consist of proximal promoters and distal enhancer regions. The coordinated activities of promoter and enhancer regions in neural stem cells (NSCs) regulate gene expression programs that produce a vast diversity of neuronal and glial cell types. In the embryonic brain, neurogenesis is accompanied by dynamic changes in chromatin accessibility and histone modifications within promoter and enhancer regions. However, the mechanisms by which epigenetic modifications in the regulatory genome of NSCs determine the complex architecture of the brain are mostly unknown.
My previous work uncovered a molecular mechanism whereby the activity of transcriptional enhancers in NSCs encodes the final position of excitatory neurons in the mouse cerebral cortex. This process depends on the activity of the chromatin-modifying enzyme known as PRDM16, a histone methyltransferase that is specifically expressed in NSCs of the embryonic cortex. My work demonstrated that PRDM16 activity is critical to regulate the epigenetic state of transcriptional enhancers and control gene expression programs during cortical neurogenesis. Enhancer activation by PRDM16 promotes amplification of neural progenitors, thereby determining the final number of cortical neurons. In contrast, enhancer silencing by PRDM16 reduces the expression of cell migration genes in NSCs, thereby controlling the final position of cortical neurons at later stages of development. Interestingly, PRDM16 is also specifically expressed in NSCs of the human brain and I have recently identified PRDM16-regulated enhancers across the entire genome of human NSCs (unpublished data). Although this work provides important insights into how epigenetic regulation of developmental enhancers in NSCs encodes the complex organization of the mammalian cerebral cortex, much work is still needed to fully understand these biological processes and their implications for human disease.
The main goal of my lab is to understand how genome-wide epigenetic modifications in NSCs and cortical neurons determine the organization and function of the cerebral cortex and the importance of these biological processes in human neurodevelopmental disorders. We use the developing mouse cerebral cortex as a model system in combination with a wide array of molecular, biochemical, genomic and cell/developmental biology techniques. Our specific research interests include:
- The role of chromatin-modifying complexes in cortical development.
- Evolution of transcriptional and epigenetic regulation in NSCs.
- Epigenetic reprogramming of gene expression in NSCs to elucidate the mechanisms that originate neuronal diversity in the cortex.
- The functional role of genome-wide chromatin modifications in directing cell fate and maintaining neuronal identity.
Chromatin, Chromosomes, and Genome Integrity
Developmental Mechanisms and Regulation in Eukaryotic Systems
Genomics and Bioinformatics