Overview: The human genome encodes ~2000 transcription factors (TFs). TFs play crucial roles in regulating various cellular mechanisms and are key regulators of numerous biological processes, which are associated with a wide range of diseases and cancers. The same TF can regulate different genes in different cell types, indicating that regulatory networks are complicated and dynamic. Determining how TFs are assembled to control transcription is essential for understanding their cell-type specific roles and mapping how specific expression programs are orchestrated in complex tissues. Deeper knowledge of how TFs find their targets and control gene expression will be beneficial for our understanding of the disease- or cancer-associated genetic variations that impact these gene regulation programs. Our lab focuses on how cell-type specific transcription regulation functions in bone and how skeletal disease and bone cancer alter or hijack this regulation. Projects in the lab utilize an interdisciplinary approach that spans genetics, multi-omics, in vivo and in vitro models to elucidate the underlying mechanisms and identify new strategies to treat bone disease and cancer.
What is the osteocyte-specific role of the transcription factor SP7 in regulating skeletal disease? SP7 (encoded by the SP7 gene) is a zinc finger-containing transcription factor and its role in osteoblast differentiation has been long studied. The function of SP7 in osteocytes has been overlooked. Our previous work took a first step to show that SP7 regulates osteocyte dendrite formation. Common human SP7-associated variants are linked to bone mineral density variation and fracture risk, and patients identified with SP7 mutations present with rare skeletal dysplasia (e.g., osteogenesis imperfecta-like bone disease). To circumvent the difficulty of studying disease-causing genes in human, we generated CRISPR knockin mice to mimic the human SP7 mutation. This model will not only make important contributions to understanding the mechanisms of skeletal disease but also benefit drug development studies designed to treat human skeletal disorder.
What is the regulatory role of bone-lineage transcription factors in bone cancer? Transcription factors (TF) are critical regulators for developmental processes and are significantly involved in cancer growth. TFs contain fewer possible targets and multiple signaling pathways can converge on the same TF. Directly targeting well-validated transcription factor drivers or inhibitors of bone cancer has the potential to be much more specific in its effects. Several osteogenic TFs have been reported to suppress bone cancer progression. However, the underlying mechanisms of how these bone-lineage TFs inhibit bone cancer growth remain unknown. We focus on how bone-lineage TFs assemble the transcription machinery to regulate specific expression programs (oncogenic vs. osteogenic) to reveal their inhibitory roles in bone pathogenesis.
What are the genetic factors that govern osteocyte maturation and skeletal disease? The central role of osteocytes in orchestrating skeletal metabolism has been gradually revealed. Many pathologic or disease conditions can now be ascribed to disrupted osteocyte functions. Recent advances in genome-wide association studies and high throughput sequencing have highlighted many susceptibility genes/loci for the pathophysiology of common and rare skeletal disease. However, the causal variants and/or genes and their biological regulatory mechanisms linked to changes in bone biology are still largely unknown. Only a limited number of osteocytic genes are studied in bone disease, due to technical obstacles of obtaining osteocytes. In order to fully capture osteocyte populations (with the hope of distinguishing the population of osteocytes where dendrite formation initiates from the populations of mineralized osteocytes and mature osteocytes with dendrite fully developed) and to identify osteocyte-specific genes that drive the osteoblast-to-osteocyte transition, novel ways to obtain differentiating and mature osteocytes for multi-omics analysis (scRNA-seq, snATAC-seq, spatial transcriptomics) are needed.
How are neuronal genes repurposed in osteocyte development? Dendrites are cell membrane projections emanating from osteocyte cell bodies which establish a highly interconnected network. This complex communication network of osteocytes resembles the network of neurons in the brain. We and others have demonstrated the similarities between osteocytic and neuronal transcriptional programs. Osteocytes may repurpose neuronal molecular control pathways to regulate osteocytic dendrite formation and facilitate osteocyte connectivity and function. Therefore, leveraging knowledge from neuroscience research is likely to accelerate understanding of how the osteocyte network forms and functions at a molecular level.