Daniel Lim, MD, PhD

Core

For stem cells to make the multitude of cell types that comprise specific tissues, daughter cells need to express certain sets of genes while repressing others.  The maintenance of such lineage-specific transcriptional programs is in part regulated by chromatin structure – the “packaged” state of DNA with histone proteins.  Recently, we have shown that postnatal brain stem cells in mice require MLL1, a chromatin remodeling factor, for the generation of new neurons.  MLL1 is part of a family of enzymes that modifies chromatin to either activate or silence gene expression.   This so-called epigenetic modification can be passed on through cell division and thus live on as a kind of cellular memory of its fate.  MLL1 operates in part through the activation of a downstream gene, Dlx2, which was previously identified as important for neural cell fate.  Our data suggests that MLL1 activates Dlx2 expression by chemically modifying the chromatin at that locus, marking that gene for persistent expression.  Further investigation may reveal a broader epigenetic program that controls neural stem cell cell fate, and thus offer the means to control the generation of new neurons for therapy.

The adult brain – including that of humans – harbors a population of neural stem cells in the subventricular zone (SVZ), a layer of cells founds along the walls of the cerebral ventricles.  Throughout life, neural stem cells in the rodent SVZ give rise to neuroblasts that migrate to the olfactory bulb where they differentiate into several types of interneurons.  The human brain also maintains a large pool of glial progenitor cells that give rise to oligodendrocytes and some astrocytes.  When isolated in culture, a small percentage of these progenitors can differentiate into neurons.  From human brain specimens obtained during resection for epilepsy, we are culturing both white matter progenitors and SVZ stem cells.  Using these human cultures with gain/loss-of-function gene strategies, we are investigating the role of specific chromatin remodeling factors in self-renewal, fate specification, and lineage fidelity.  In particular, we are interested in determining whether endogenous human glial progenitors or SVZ NSCs can be “programmed” for specific neural lineages by manipulating the epigenome.