International collaborators will investigate how chromatin is spatially organized within the nucleus of various cell types and how this organization changes over time in an effort to identify targets for treating a host of diseases
Cleveland Clinic has been named a participating institution for the newly established Center for Integrated Multi-Modal and Multi-Scale Nucleome Research, made possible by a recently awarded five-year, $6.5 million consortium grant from the National Institutes of Health (NIH) Common Fund. Ming Hu, PhD, assistant staff in the Department of Quantitative Health Sciences, is a co-investigator on the grant and will lead the center’s multi-omics data analysis efforts.
This large grant is one of the latest to be funded as part of NIH’s 4D Nucleome Program, which seeks to better understand how genetic material is organized within our cells and how the spatial organization of chromatin (the material within chromosomes that contain DNA and proteins) contributes to human health and disease.
Most human DNA is housed in a very small cellular compartment called the nucleus. Despite its tiny size, the nucleus houses over six feet of DNA. Considering that so much important genetic material is packed into such a small space, its order and spatial organization must be tightly and precisely regulated. The order of nuclear DNA helps to control what genes are expressed–that is, turned “on” or “off” in a specific cell type–and abnormal DNA organization is associated with a host of diseases, including cancer, autoimmune diseases, developmental disorders, neuropsychiatric disorders and many age-related conditions.
Like other projects funded through the 4D Nucleome Program, the Center for Integrated Multi-Modal and Multi-Scale Nucleome Research, which will be led by Bing Ren, PhD, University of California, San Diego (UCSD), seeks to understand how changes in nuclear DNA organization over time may contribute to the onset and progression of various diseases. Gaining a more comprehensive understanding of these changes over time–considered the fourth dimension–will enable the identification of new targets for treating a range of diseases.
More specifically, with this new award, the team of researchers will work to develop navigable reference maps of chromatin architecture across multiple cell types found in the brains of humans and several types of preclinical models.
Dr. Hu will lead multiple integrative data analyses to better understand: how interactions between gene promoters and enhancers (regulatory sequences of DNA) affect gene expression at single-cell resolution; how regulators of gene transcription, including enhancers and promoters, control gene expression in a cell-type-specific manner; and how to prioritize disease risk genes in disease-relevant cell types. Dr. Hu will make use of several data types, including single-cell multi-omics, imaging and genome-wide association datasets.
In addition to Cleveland Clinic and UCSD, other participating institutions include: Harvard University; Allen Brain Institute; Universita’ di Napoli “Frederico II”, Italy; Max Delbrück Center for Molecular Medicine, Berlin, Germany; Salk Institute; and Washington University, St. Louis.
In accordance with 4D Nucleome Program standards, all resultant references maps, analytical tools, visualization methods and structural models will be freely shared with the broader scientific community to help speed research translation. While funded by the NIH Common Fund, this grant (UM1HG011585) is administered through the National Human Genome Research Institute.