Overview: The human genome encodes approximately 2,000 transcription factors (TFs), which play critical roles in regulating diverse cellular processes and are key drivers of many biological functions linked to a wide range of diseases and cancers. A single TF can regulate different genes depending on the cell type, highlighting the complexity and dynamic nature of regulatory networks. Understanding how TFs assemble to control transcription is crucial for elucidating their cell-type–specific functions and for mapping the expression programs that coordinate complex tissue biology. Greater insight into how TFs locate their targets and regulate gene expression will enhance our understanding of disease- and cancer-associated genetic variations that disrupt these regulatory programs. Our lab focuses on cell-type–specific transcriptional regulation in bone, investigating how skeletal diseases and bone cancer alter or hijack these regulatory mechanisms. Using an interdisciplinary approach that combines genetics, multi-omics, and both in vivo and in vitro models, our projects aim to uncover underlying mechanisms and identify novel strategies to treat bone diseases and cancer.
What is the specific role of the transcription factor SP7 in osteocytes in regulating skeletal diseases? SP7, encoded by the SP7 gene, is a zinc finger transcription factor whose role in osteoblast differentiation has been extensively studied. However, its function in osteocytes has received little attention. Our previous research was the first to demonstrate that SP7 plays a critical role in osteocyte formation and differentiation. Common human variants of SP7 are associated with variations in bone mineral density and fracture risk, while mutations in SP7 cause rare skeletal disorders, such as osteogenesis imperfecta-like bone disease. To overcome the challenges of studying disease-causing genes in humans, we developed CRISPR knockin mouse models that replicate the human SP7 mutation. This model not only advances our understanding of skeletal disease mechanisms but also serves as a valuable platform for drug development aimed at treating human skeletal disorders.
What is the role of lineage-specific transcription factors in driving or regulating bone cancer progression? Transcription factors (TFs) are key regulators of developmental processes and play pivotal roles in cancer progression. Targeting well-characterized transcriptional drivers or inhibitors of bone cancer holds promise for achieving greater therapeutic specificity. Several osteogenic TFs have been shown to suppress bone cancer progression, yet the mechanisms by which these bone-lineage transcription factors exert their inhibitory effects remain largely unclear. We aim to investigate the potential of bone-lineage specific transcription factors to restore osteogenic differentiation in tumor cells, as well as to elucidate novel targetable pathways for the treatment of bone cancer.
What are the key genetic regulators of osteocyte maturation, and how do they contribute to skeletal disease mechanisms? The central role of osteocytes in regulating skeletal metabolism has become increasingly clear, with numerous pathological conditions now linked to impaired osteocyte function. Advances in genome-wide association studies (GWAS) and high-throughput sequencing have identified multiple genetic loci associated with both common and rare skeletal diseases. However, the specific causal variants, genes, and underlying regulatory mechanisms affecting bone biology remain largely uncharacterized. Progress in this area has been limited in part by technical challenges in isolating osteocytes, resulting in relatively few osteocyte-specific genes being studied in the context of bone disease. To comprehensively capture the osteocyte population—including early-stage cells initiating dendrite formation, mineralizing osteocytes, and fully mature dendritic osteocytes—novel methods are needed to isolate differentiating and mature osteocytes for multi-omics analyses, such as scRNA-seq, snATAC-seq, and spatial transcriptomics. These approaches will be critical for identifying key genes that govern the osteoblast-to-osteocyte transition and for advancing our understanding of osteocyte biology in skeletal disease.
What are the mechanisms by which neuronal genes are co-opted for osteocyte development? Osteocyte dendrites are membrane projections that extend from the cell body, forming an intricate and highly interconnected cellular network. This structural organization closely parallels the neural networks found in the brain. Our work, along with that of others, has revealed striking similarities between the transcriptional programs of osteocytes and neurons. These findings suggest that osteocytes may co-opt neuronal molecular pathways to regulate dendrite formation and maintain intercellular connectivity and function. As such, applying insights from neuroscience holds significant potential to deepen our understanding of the molecular mechanisms underlying osteocyte network development and activity.