Epigenetic modifier directed therapeutics to unleash healthy genes in unhealthy cells

Abstract

A common thread through malignant and nonmalignant diseases alerts us to a therapeutic opportunity to seize: disease may originate from genetic mutations, but resulting maladaptive/unhealthy cell fates and functions are mediated by epigenetic enzymes, that are druggable. Epigenetic enzymes modify DNA, and/or the histones around which DNA is organized, to regulate access to genes by the basal transcription factor machinery that transcribes genes. Epigenetic enzymes can be divided usefully into those that facilitate gene transcription ("on" enzymes or coactivators) and those that favor gene repression ("off" enzymes or corepressors). DNA-binding master transcription factors cooperate to recruit coactivators, and repulse corepressors, from thousands of genes, to thereby activate the gene expression programs that define cell fates and functions. In malignancy, this usual exchange of corepressors for coactivators fails, because of mutations to master transcription factors or the coactivators they recruit. Inhibiting corepressor enzymes using small molecules uses pharmacology to redress this coactivator/corepressor imbalance that originates from genetics, to in this way release cancer cells to the terminal lineage-fates intended by their master transcription factor content. Similarly, in nonmalignant β-hemoglobinopathies, inhibiting corepressors exploits transcription factor and lineage-context to activate unmutated fetal over mutated adult globin genes, to thereby treat these nonmalignant genetic diseases. Master transcription factors then are the "natural forces" in the Hippocratic dictum "Natural forces within us are the true healers of disease," and drugging epigenetic enzymes (corepressors) a way to harness these forces to heal.

Keywords: Cancer; Epigenetics; Hemoglobinopathy; Leukemia; Therapy.

Figure.. The cell fate/function consequences of inhibiting corepressors, for example, depleting DNMT1 using the clinical drug decitabine, depend on lineage and maturation (master transcription factor, TF) context.

(A) Relevance to malignancies using acute myeloid leukemia (AML) as an example: AML cells cluster with committed myeloid progenitors (common myeloid progenitors/CMP, granulocyte-monocyte progenitors/GMP) and terminally-differentiated myeloid lineages (granulocytes/Gran and monocytes/Mono) by TF content. Thus, inhibiting recruited corepressors in AML cells, as in normal committed progenitors, induces terminal-differentiation; treating hematopoietic stem cells (HSC) the same way increases self-renewal, since these express HSC TF. The AML samples contained normal, complex or t(11;9) cytogenetics (10 of each, public data BloodSpot). A more comprehensive unbiased clustering analyses was previously shown in [13] and similar analyses in other cancers is in [4]. (B) Relevance to β-hemoglobinopathies: The consequences of targeting corepressors, for example, DNMT1, in erythroid lineage (Ery.) cells depend on maturation stage in this lineage; fortuitously, some cells in vivo are always at a stage whereby the switch from fetal hemoglobin (HBG1, HBG2) to adult hemoglobin (HBB) production can be prevented without impeding onward erythroid maturation. Gene expression by RNA sequencing (public data GSE74482) in human hematopoietic progenitors cultured in an erythroid differentiation system. (C) Inhibiting corepressors recruited into TF hubs in unhealthy cells can harness the TF as “natural forces,” to drive the cells toward more adaptive cell fates and functions. Some corepressors, for example, histone deacetylases (HDAC) and likely KDM1A, have nonepigenetic functions also, thus even on-target actions of drugs can have unintended side-effects. Other corepressors for which there are available small molecule inhibitors, for example, EZH2, may not be routinely recruited into TF hubs. Some corepressors, for example, DNA and histone demethylases, can be modulated by drugs that impact their mandatory cofactors (eg, alpha ketoglutarate/AKG, cytidine triphosphate/CTP, nicotinamide adenine dinucleotide/NAD⁺).