Transgenerational Epigenetic DNA Methylation Editing and Human Disease

During gestation, maternal (F0), embryonic (F1), and migrating primordial germ cell (F2) genomes can be simultaneously exposed to environmental influences. Accumulating evidence suggests that operating epi- or above the genetic DNA sequence, covalent DNA methylation (DNAme) can be recorded onto DNA in response to environmental insults, some sites which escape normal germline erasure. These appear to intrinsically regulate future disease propensity, even transgenerationally. Thus, an organism's genome can undergo epigenetic adjustment based on environmental influences experienced by prior generations. During the earliest stages of mammalian development, the three-dimensional presentation of the genome is dramatically changed, and DNAme is removed genome wide. Why, then, do some pathological DNAme patterns appear to be heritable? Are these correctable? In the following sections, I review concepts of transgenerational epigenetics and recent work towards programming transgenerational DNAme. A framework for editing heritable DNAme and challenges are discussed, and ethics in human research is introduced.