Stable silencing of spinal motor neuron enhancers by transiently expressed Nkx2.2

Columbia University Health Sciences, New York NY

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Abstract

? DESCRIPTION (provided by applicant): The hallmark of multicellular organism development is concerted differentiation of pluripotent cells into diverse postmitotic cell types. This process relies on transcriptional programs that in a coordinated manner activate expression of terminal effector genes and repress genes expressed in other lineages. While progress has been made in identifying transcriptional activators and mechanisms through which they establish new cell identities, little is currently known about the process underlying progressive repression of alternative developmental programs. Specifically, many transcriptional repressors that control differentiation of neural cells are expressed only transiently during early patterning of neuroepithelium and it has not been determined whether these repressors act solely on genes expressed in neural progenitors or whether they can silence enhancers in a persistent fashion to prospectively modify gene expression even following their downregualtion. Here we will examine effects of a transiently expressed motor neuron repressor Nkx2.2 on chromatin modifications of enhancers it binds and on patterns of gene expression in mouse motor neuron progenitors (while Nkx2.2 is ectopically expressed) and following its downregulation. Function of Nkx2.2 in enhancers that are stably silenced will be experimentally tested by deletion of Nkx2.2 binding motif. Together these studies will reveal fundamental mechanisms underlying stable silencing of poised or active enhancers during terminal differentiation of cells in multicellular organisms. As silenced enhancers need to be reverted into an active or poised state during cell fate reprogramming, our findings might be instrumental for the development of more efficient patient cell reprogramming strategies for diagnostic and therapeutic purposes.