Heterochromatin as a barrier to regeneration in the mouse cochlea

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PROJECT SUMMARY/ABSTRACT The main cause of hearing loss is damage of cochlear sensory hair cells within the inner ear. The long-term objective of the Segil lab is to treat human deafness through the regeneration of lost sensory hair cells within the organ of Corti. A potential strategy for hair cell regeneration is to induce surviving supporting cells in long- deafened inner ears to transdifferentiate into new functional hair cells. In early perinatal mice, upregulation of the hair-cell specific transcription factor ATOH1, or disruption of Notch lateral inhibition in supporting cells, is sufficient to induce transdifferentiation. However, supporting cells quickly lose the potential to transdifferentiate within one week after birth. The loss of this plasticity may be due to epigenetic maturation, wherein the spread of heterochromatin in perinatal supporting cells represses hair cell- specific gene regulatory networks required for transdifferentiation. Heterochromatin are highly condensed regions of nuclear DNA associated with gene silencing, and it has cell-type specific characteristics that acquires during development. Epigenetic marks of heterochromatin include DNA methylation, H3K9 methylation, and H3K27 methylation. My preliminary data shows that blocking DNA methylation is sufficient to prolong the window of transdifferentiation potential in postnatally maturing supporting cells. Additionally, I have shown that SCs gradually gain DNA methylation as they mature from P1 to P21. This project hypothesizes that postnatally maturing supporting cells gain heterochromatin-associated DNA methylation and H3K9 methylation to repress hair cell gene regulatory networks required for transdifferentiation. Aim 1 will characterize the changes in DNA methylation between postnatal day 1 and 6-week old supporting cells of the organ of Corti, as well as test the DAPT-induced transdifferentiation response after blocking DNA methylation gain. Aim 2 will examine the changes in H3K9 methylation between postnatal day 1 and 6-week old supporting cells, as well as test the DAPT-induced transdifferentiation response after blocking H3K9 methylation gain. These two aims will elucidate how the spread of heterochromatic features in postnatally maturing supporting cells may contribute to the loss of transdifferentiation potential, which will which will guide future endeavors to regenerate hair cells and restore hearing.