Mitochondrial Epigenetics and Environmental Health: Making a Case for Endocrine Disrupting Chemicals

Recent studies implicate mitochondrial dysfunction in the development and progression of numerous chronic diseases, which may be partially due to modifications in mitochondrial DNA (mtDNA). There is also mounting evidence that epigenetic modifications to mtDNA may be an additional layer of regulation that controls mitochondrial biogenesis and function. Several environmental factors (eg, smoking, air pollution) have been associated with altered mtDNA methylation in a handful of mechanistic studies and in observational human studies. However, little is understood about other environmental contaminants that induce mtDNA epigenetic changes. Numerous environmental toxicants are classified as endocrine disrupting chemicals (EDCs). Beyond their actions on hormonal pathways, EDC exposure is associated with elevated oxidative stress, which may occur through or result in mitochondrial dysfunction. Although only a few studies have assessed the impacts of EDCs on mtDNA methylation, the current review provides reasons to consider mtDNA epigenetic disruption as a mechanism of action of EDCs and reviews potential limitations related to currently available evidence. First, there is sufficient evidence that EDCs (including bisphenols and phthalates) directly target mitochondrial function, and more direct evidence is needed to connect this to mtDNA methylation. Second, these and other EDCs are potent modulators of nuclear DNA epigenetics, including DNA methylation and histone modifications. Finally, EDCs have been shown to disrupt several modulators of mtDNA methylation, including DNA methyltransferases and the mitochondrial transcription factor A/nuclear respiratory factor 1 pathway. Taken together, these studies highlight the need for future research evaluating mtDNA epigenetic disruption by EDCs and to detail specific mechanisms responsible for such disruptions.

LncRNAs as Chromatin Regulators in Cancer: From Molecular Function to Clinical Potential

During the last decade, high-throughput sequencing efforts in the fields of transcriptomics and epigenomics have shed light on the noncoding part of the transcriptome and its potential role in human disease. Regulatory noncoding RNAs are broadly divided into short and long noncoding transcripts. The latter, also known as lncRNAs, are defined as transcripts longer than 200 nucleotides with low or no protein-coding potential. LncRNAs form a diverse group of transcripts that regulate vital cellular functions through interactions with proteins, chromatin, and even RNA itself. Notably, an important regulatory aspect of these RNA species is their association with the epigenetic machinery and the recruitment of its regulatory apparatus to specific loci, resulting in DNA methylation and/or post-translational modifications of histones. Such epigenetic modifications play a pivotal role in maintaining the active or inactive transcriptional state of chromatin and are crucial regulators of normal cellular development and tissue-specific gene expression. Evidently, aberrant expression of lncRNAs that interact with epigenetic modifiers can cause severe epigenetic disruption and is thus is closely associated with altered gene function, cellular dysregulation, and malignant transformation. Here, we survey the latest breakthroughs concerning the role of lncRNAs interacting with the epigenetic machinery in various forms of cancer.

Cutting Edge Therapeutic Insights Derived from Molecular Biology of Pediatric High-Grade Glioma and Diffuse Intrinsic Pontine Glioma (DIPG)

Pediatric high-grade glioma (pHGG) and brainstem gliomas are some of the most challenging cancers to treat in children, with no effective therapies and 5-year survival at ~2% for diffuse intrinsic pontine glioma (DIPG) patients. The standard of care for pHGG as a whole remains surgery and radiation combined with chemotherapy, while radiation alone is standard treatment for DIPG. Unfortunately, these therapies lack specificity for malignant glioma cells and have few to no reliable biomarkers of efficacy. Recent discoveries have revealed that epigenetic disruption by highly conserved mutations in DNA-packaging histone proteins in pHGG, especially DIPG, contribute to the aggressive nature of these cancers. In this review we pose unanswered questions and address unexplored mechanisms in pre-clinical models and clinical trial data from pHGG patients. Particular focus will be paid towards therapeutics targeting chromatin modifiers and other epigenetic vulnerabilities that can be exploited for pHGG therapy. Further delineation of rational therapeutic combinations has strong potential to drive development of safe and efficacious treatments for pHGG patients.

Accepted manuscript, Nat Comms.

Food allergy poses a significant clinical and public health burden affecting 2-10% of infants. Using integrated DNA methylation and transcriptomic profiling, we found that polyclonal activation of naïve CD4+ T-cells through the T-cell receptor resulted in poorer lymphoproliferative responses in children with IgE-mediated food allergy. Reduced expression of cell cycle related targets of the E2F and MYC transcription factor networks, and remodeling of DNA methylation at metabolic (RPTOR, PIK3D, MAPK1, FOXO1) and inflammatory genes (IL1R, IL18RAP, CD82) underpins this suboptimal response. Infants who fail to resolve food allergy in later childhood exhibit cumulative increases in epigenetic disruption at T-cell activation genes and poorer lymphoproliferative responses compared to children who resolved food allergy. Our data indicate epigenetic dysregulation in the early stages of signal transduction through the T-cell receptor complex, and likely reflects pathways modified by gene-environment interactions in food allergy.

Massive Factorial Design Untangles Coding Sequences Determinants of Translation Efficacy

Comparative analyses of natural sequences or variant libraries are often used to infer mechanisms of expression, activity and evolution. Contingent selective histories and small sample sizes can profoundly bias such approaches. Both limitations can be lifted using precise design of large-scale DNA synthesis. Here, we precisely design 5E. coligenomes worth of synthetic DNA to untangle the relative contributions of 8 interlaced sequence properties described independently as major determinants of translation inEscherichia coli. To expose hierarchical effects, we engineer an inducible translational coupling device enabling epigenetic disruption of mRNA secondary structures. We find that properties commonly believed to modulate translation generally explain less than a third of the variation in protein production. We describe dominant effects of mRNA structures over codon composition on both initiation and elongation, and previously uncharacterized relationships among factors controlling translation. These results advance our understanding of translation efficiency and expose critical design challenges.