Transposable Elements as Mechano-Response Enhancer Elements Regulating hESC Fate

About This Grant

ABSTRACT Transposable elements (TEs) make up over half of the human genome and are increasingly recognized as key regulatory sequences of gene expression in development and disease. While cellular intrinsic transcriptional and epigenetic mechanisms controlling TE sequences are well-documented, whether and how TEs response to external microenvironmental signals, particularly mechanical forces, remains unexplored. This represents a critical gap in understanding both TE regulation and genome–environment interactions. Our preliminary data reveal that several TE families, including LTR7 from the primate-specific HERV-H family, function as Mechano-Response Enhancer Elements (MREEs) that regulate gene expression and human pluripotent stem cell fate in response to mechanical stimuli. Additional preliminary findings support our central hypothesis that TEs act as MREEs by modulating human genes and cell fate of human pluripotent stem cells through a mechanism at least partially governed by the key mechano-effector YAP, which regulates TEs’ local epigenetic activity and facilitates their long-range chromatin looping with target genes in response to mechanical changes. To test this model, we propose three specific aims: 1) determine how mechanical signals regulate the local chromatin activity of TE MREEs; 2) elucidate how mechanical cues mediate long-range chromatin interactions between TE MREEs and their distal target genes; 3) delineate the mechanism by which TE MREE modulating human embryonic stem cell fate. Our objective is to rigorously establish the novel concept that TEs function as MREEs, uncover their underlying molecular mechanisms, and assess their biological significance in regulating developmental genes and hESC fate. The expected outcome will not only shift the current paradigm of mechanobiology from protein- coding genes to non-coding regulatory elements such as TE but also improve our understanding of TE regulation and genome-environment interactions in health and disease.