Lysine-specific demethylase 1 (LSD1, KDM1A) confers transcriptional repression by demethylating H3K4 or activating transcription by demethylating H3K9.  Howerver, the role of LSD1 in regulating osteoclast differentiation is unknown,  The Mansky lab has determined that LSD1cKO mice have smaller osteoclasts and increased BV/TV compared to LSD1WT mice.  Bulk RNA-SEQ of femur-derived osteoclast precursors from LSD1cKO mice indicate that genes in the IFN-beta pathway are upregulated compared to LSD1WT cells.  Further, LSD1cKO mice do not lose bone in a ligature induced periodontitis model or an arthritis model compared to their LSD1WT littermates.  Current questions in the lab include how does age affect LSD1WT and LSD1cKO regulation of osteoclasts in a ligature induced periondontitis model? What genes do LSD1 target in maladaptive innate immune training? What genes does HDAC1 and 2 target when complexed to LSD1? 

Craniofacial osteoclasts are essential for site-specific processes such as alveolar bone resorption, tooth eruption, and orthodontic tooth movement. Much of the current understanding of osteoclast development and function comes from studies using long bone derived cells. Minimal investigation has been done to explore skeletal site differences. It was shown that mandibular-derived osteoclasts have enhanced size (mm2) compared to femoral-derived osteoclasts. Monocyte genes such as Pu.1, C/ebp-a, and Prdm1 are increased in expression in mandibular-derived monocytes compared to femoral-derived monocytes. As expected with enhanced differentiation, osteoclast genes including Nfatc1, Dc-stamp, Ctsk, and Rank are upregulated in mandibular-derived osteoclast precursors. Next we performed scRNA-seq on femur and mandible-derived myeloid cells. Our results reveal transcriptomic evidence that suggests a uniquely inflammatory genetic profile of the mandibular-derived myeloid cells. This monocyte population had enhanced inflammatory gene expression by qRT-PCR which correlated  with an increase in select areas of open chromatin by ATAC-Sequencing. Further exploration into a specific upregulated gene determined KLF4 was both necessary and important for proper differentiation in mandibular- but not femur-derived cells.   Current research questions include: Does KLF4 differentially regulate mandible and femur-derived osteoclasts? Is lactylation involved in regulating gene expression in mandibular-derived osteoclasts?