While genetic information encoded by DNA provides a framework for gene expression, epigenetic regulation is equally critical for physiological responsiveness to extracellular cues. Our laboratory pioneered examining the chromatin structure of several key gene loci (e.g., histone H4, osteocalcin, Runx2) to understand how architectural and topological constraints on gene promoters and enhancers at distal regulatory sites in chromatin contribute to epigenetic control of gene expression. These studies have evolved into detailed molecular analyses of histone modifications (e.g., H4 acetylation, H3 methylation), SWI/SNF related chromatin remodeling and genome-wide transcription factor binding analyses using ChIP-on-chip and ChIP-Seq approaches (see Nuclear Structure and Function).
Beyond the conventional epigenetic mechanisms that include post-transcriptional modifications of histones, and methylation of CpG moieties in gene promoters, we have identified a unique epigenetic mechanism, where phenotypic transcription factors remain associated with target genes during mitosis. This association, termed architectural epigenetics (‘Bookmarking’) ensures that the progeny cells maintain the cell growth and proliferative potential, as well as remain committed to lineage of the parent cells. We are actively exploring mechanisms that ensure sustained architectural epigenetics during symmetrical division of committed cells and during asymmetrical mitosis of stem cells.
Another epigenetic mechanism that has become a focus of our research group is the involvement of non-coding RNAs, microRNAs, and long non-coding RNAs, in regulating osteoblast- and hematopoiesis-related gene expression. We have carried out genome-wide screens for the expression of miRs and long non-coding RNAs under various physiological conditions and have identified miR signatures that have the potential to predict a biological response or a pathological outcome. Our group is further dissecting roles of these non-coding RNA signatures in osteoblastogenesis (see Musculoskeletal Biology and Pathology) and hematopoeisis, as well as in human leukemia. We have identified a mitotically associated long non-coding RNA in triple-negative breast cancer cells designated MANCR that is required to stabilize the breast cancer-compromised genome. Based on our discovery that knock-out of MANCR in triple-negative breast cancer cells results in apoptosis/cell death we are investigating MANCR knock-out as a targeted strategy for triple-negative breast cancer in vivo utilizing a xenograft mouse mode.
Our research group was among the first to investigate cancer-compromised epigenetic control of gene expression during the onset of progression of breast cancer. In a tumor progression breast cancer cell culture model we have leverage chromosome conformation capture approaches to identify cancer-compromised modifications in higher-order chromatin organization. We have directly confirmed breast cancer-compromised inter and intrachromosomal interaction by multispectral imaging. We are mechanistically defining epigenetic control of aberrant chromatin organization in breast cancer cells by genomic strategies that identify histone modifications and DNA methylation. Initial epigenetic responses to degron ablation of the RUNX1 tumor suppressor in mammary epithelial cells is providing the first direct indication of regulatory consequences that are functionally linked with breast cancer initiation. We are pursuing clinically relevant validation of our findings by multi-omic and spatial transcriptomic analysis of patient-derived breast tumors.