At the cellular level, we focus on nuclear architecture as it supports proliferation and differentiation of lineage-committed cells and stem cells, as well as compromised nuclear structure and higher order genomic and chromatin organization that characterizes cancer cells. These studies utilize multiomic strategies analyze subnuclear organization of gene regulatory machinery including intranuclear trafficking of transcription factors, interactions with cell-signaling responsive co-factors and chromatin remodeling enzymes. We apply systems biology approaches to define integrated gene regulatory networks and signaling pathways. Multispectral imaging supports investigation and characterization of genes, transcripts, and regulatory proteins for biological control and during cancer initiation and progression. 

At the molecular level, we are defining epigenetic chromatin modifications at gene loci during interphase (‘Histone Code’) and mitosis (‘Bookmarking’) to understand the epigenetically-mediated transcriptional regulation of tissue-specific genes, cell cycle control, and cell fate determination. Our studies center on transcriptional master regulators and post-transcriptional mechanisms (including microRNAs and non-long-coding RNAs) that together control osteogenesis, hematopoiesis, and the pluripotent state of embryonic stem cells. The aberrant loss- or gain-of-function of these gene regulatory factors in leukemias, as well as in metastasizing breast, prostate, and bone cancers, are being actively pursued. Inter and intrachromosomal interactions are being identified that contribute to the higher-order chromatin organization, which is a rapidly developing dimension to control of gene expression for biological regulation and pathology. Spatial transcriptomic analysis and single-cell genomic and epigenomic strategies are supporting the characterization of cross-talk between breast cancer cells and the tumour microenvironment. The organization and assembly of regulatory machinery for gene expression in liquid phase-seperated domains is being investigated by genomic and imaging strategies.

Experimental systems include CRISPR-edited cell lines and mouse models, cancer stem cells, cancer patient-derived organoids, and xenografts. Experimental approaches include genome analysis (single-cell sequencing, degron protein ablation technology, RNA-seq, ATAC-seq, CHiRP, CHiRP Mass Spec, PRO-seq, Cut and Run, Radical Seq, BioID, and chromosome conformation capture and Micro C), spatial transcriptomics (NanoString), multispectral imaging (CODEX), degron strategies, and analysis of patient-derived tissue specimens.