Accordingly, I have 3 specific objectives of this proposal: i) I plan to carry out a comprehensive in vitro epi-drug screen to determine which enzymatic targets have the greatest anti-neoplastic activity; from this, ii) I will characterize the epigenomic changes that underpin such phenotypic rescue; finally, iii) I will compare the therapeutic effects of the top global-acting epi-drug versus target-specific epigenetic editing (Epi-CRISPR) of the most recurrent epimutation
LE: SENS Foundation has been investigating the possibility that mutation and epimutation
(changes in gene expression rather than alterations of the genes themselves) may be deleterious in ways other than cancer.
Evidence of constitutional MLH1 epimutation
associated to transgenerational inheritance of cancer susceptibility.
5) That is, the initial exposure to DDT may have caused an epimutation
in a would-be parent and this aberrant pattern was later inherited.
A rare constitutional epimutation
of MLH1 has also been reported, (47) potentially adding even further complexity to genetic testing for LS.
of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome.
Allelespecific germ cell epimutation
in the spacer promoter of the 45S ribosomal RNA gene after Cr(III) exposure.
Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations
Hydrocarbons (jet fuel JP-8) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations
2008) Deletions and epimutations
affecting the human chromosome 14q32.
Of note, cases of constitutional MLH1 epimutations
have been described where the promoter of one MLH1 allele is hypermethylated in the germline, resulting in transcriptional silencing of the allele in nonneoplastic tissue.
This understanding may allow for improvement of healthy aging by reversing disease-prone epimutations
involved in chronic inflammatory and metabolic disorders.