Understanding how defects in the maternal epigenetic reprogramming function of LSD1/KDM1A contribute to inherited phenotypes

At fertilization, histone modifying enzymes drive massive maternal epigenetic reprogramming that is vital for appropriate embryonic and postnatal development. In C. elegans and mouse, the lysine specific demethylase 1 (LSD1/KDM1A) acts as a repressor during this reprogramming by removing H3K4me1/2 and preventing the inappropriate inheritance of active transcriptional patterns to the progeny. In mouse, our lab has shown that LSD1 is required maternally to erase H3K4me1/2 at fertilization, enabling the switch from maternal to zygotic transcription. The maternal loss of LSD1 results in embryonic arrest at the 2-cell stage, stemming from a failure to repress maternal/oocyte genes, suggesting that maternal LSD1 epigenetic reprogramming is essential for embryogenesis to proceed. However, it is unclear how histone modifying enzymes are regulated during maternal reprogramming and whether defects in this reprogramming can lead to inherited disease. To address these questions and bypass the 2-cell arrest, we developed a hypomorphic allele of Lsd1, that predominantly affects the binding of LSD1 to its maternal partner CoREST. Data from this new model show that progeny from mothers with maternally hypomorphic Lsd1 exhibit increased perinatal lethality, as well as developmental delay, craniofacial abnormalities, and potential behavior defects. This suggests that the maternal function of LSD1 is CoREST dependent and that partial loss of LSD1 can lead to inherited phenotypes. de novo mutations in LSD1/KDM1A and in Kabuki Syndrome, which is caused by mutations in related histone methylation enzymes, lead to neurodevelopmental disorders, characterized by developmental delay, craniofacial defects and behavioral abnormalities. Intriguingly, the overlap in phenotypes of the human patients and our hypomorphic Lsd1 progeny raises the exciting possibility that a defect in maternal reprogramming may contribute to disease in these patients. To determine how partially compromised maternal LSD1 reprogramming leads to perinatal lethality, developmental delay, and craniofacial abnormalities, I will utilize our new mouse model in which LSD1 is partially compromised only maternally. Using this mouse model, I will determine if compromised maternal Lsd1 at fertilization leads directly to phenotypes in the progeny by examining changes in gene expression and inappropriate H3K4me2 retention. I will also investigate whether compromised maternal Lsd1 at fertilization leads indirectly to phenotypes by examining DNA methylation. Combining the analyses of these aims will give me a wholistic view of how compromised maternal LSD1 reprogramming gives rise to phenotypes observed in patients with mutations in histone modifying enzymes. Understanding this etiology is essential if we are to develop therapeutic treatments in the future. Project Number: 1F31HD116544-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Monica Reeves | Institution: EMORY UNIVERSITY, ATLANTA, GA | Award Amount: $49,538 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F05-E (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31HD11654401A1