REST function during mouse nervous system development

Intraventricular glioblastoma in a brain section from an adult mouse

The transcriptional repressor, REST, was identified originally in our lab as a master regulator of neuronal gene expression. It has served as a model for understanding many fundamental aspects of gene expression, including the first proof of principal for high throughput chromatin immunopreciptation analysis (ChIP seq) and the first example of a specialized chromatin landscape in neural progenitors. Once thought to play a role primarily in non-neuronal cells outside the nervous system, more recent studies, using a new REST knock out mouse we generated, indicate an important role in in protecting genomic integrity in neural progenitor cells during embryonic development. Loss of REST prematurely results in aggressive glioblastoma due to the damage. We are currently investigating the basis of these protective mechanisms.

Figure legend: Brain section from an adult mouse showing intraventricular glioblastoma (blue) arising from DNA damage in neural progenitors that have lost REST prematurely during CNS development. Asterisks indicate areas of necrosis. Image from Nechiporuk et al., 2016.

REST function in human postnatal brain development and cognition

A relatively new topic of interest in the lab is study of the molecular basis for cognitive decline. Our recent bioinformatics investigation of global REST binding sites in human chromatin has revealed a surprising amount of differences between human and mouse genomes. For example, we have identified the acquisition of REST binding sites in genes in human brain that are not present in the same genes in mouse. This difference likely reflects the higher sophistication of the human brain, and we are performing studies to understand the roles of REST in regulating gene expression during the aging process. We work closely with an OHSU neuropathologist, Dr. Randy Woltjer, in this work, as well as with a colleague working on induced neurons from fibroblasts from patients of different ages.

MECP2 function and Rett Syndrome: neurons, glia and approaching a cure

Graphic representation of a single cell analysis of nuclei isolated from mouse hippocampus

Figure legend: A single cell analysis of nuclei isolated from mouse hippocampus identifies nine distinct cell populations, D1-D9, based on published RNA profiling data, and resolved using a bioinformatics pipeline developed in the Adey lab. Image from Sinnamon et al., 2019.

For over a decade, we have been researching the molecular and cellular bases for the neurological disease Rett Syndrome. Rett is due to sporadic mutations in the transcription factor, MeCP2. Unlike many other neurological diseases, Rett does not cause overt neuronal degeneration, and is reversible in mouse models by restoring a normal copy of MeCP2. Once thought to be a disease exclusively of neurons, we found that astrocytes are also affected, and restoring MeCP2 just in astrocytes, in a global Rett mouse model, greatly diminishes the progression of symptoms. In collaboration with the Brehm lab, we have performed physiology and calcium imaging in cortical brain slices from our mouse models. The work reveals how astrocytes modify neuronal circuitry in normal brain and brain from Rett mouse models. We are also collaborating with Dr. Andrew Adey, in the Department of Molecular and Medical Genetics at OHSU, on developing single cell chromatin analysis pipelines to identify the basis for differential gene expression in glial and neuronal cell types in normal and Rett brain. Finally, we are developing a novel approach, site directed RNA editing, to repair MeCP2 mutations in vivo. This work is done in collaboration with the Nakai group, at OHSU, to fine tune gene delivery of the RNA editing components to the nervous system of our mouse models.