Metabolic Inputs into the Epigenome Upasna Sharma, Oliver J. Rando  Cell Metabolism  Volume 25, Issue 3, Pages 544-558 (March 2017) DOI: 10.1016/j.cmet.2017.02.003 Copyright © 2017 Terms and Conditions

Figure 1 Metabolic Inputs into DNA Cytosine Methylation and Chromatin Overview of three broad mechanisms by which metabolites can affect DNA cytosine methylation or chromatin structure. As the regulators of cytosine methylation and chromatin share a great deal in common—both marks are associated with the genome, and metabolites such as SAM and α-KG affect methylation/demethylation of both DNA and the histone proteins—these epigenetic marks are shown together for convenience. (A) Metabolic signaling can affect the expression or activity of the enzymes that modify DNA or chromatin, or of proteins that otherwise play central roles in epigenetic modification. Altered levels of these regulatory factors can then lead to global changes in DNA cytosine methylation or chromatin. While this image shows transcriptional effects on CRs, metabolic signaling can also affect levels of these proteins, or activity of these proteins, post-transcriptionally. (B) Metabolites can modulate DNA methylation and chromatin at specific genomic loci by affecting the activity/localization of proteins that recruit or regulate DNA- and chromatin-modifying enzymes. A simple case of this is seen in the recruitment of chromatin regulators during transcriptional activation, for instance. (C) Finally, cellular metabolite pools serve as the substrates and cofactors for DNA- and chromatin-modifying enzymes, and changes in levels of these metabolites can in turn lead to global changes in chromatin and DNA modifications. CR, chromatin regulator; TF, transcription factor; HMT, histone methyl transferase; HAT, histone acetyl transferase; DMT, DNA methyltransferase; SAM, S-adenosyl methionine; Acetyl-CoA, acetyl-coenzyme A; NAD+, nicotinamide adenine dinucleotide; a-KG, α-ketoglutarate. Cell Metabolism 2017 25, 544-558DOI: (10.1016/j.cmet.2017.02.003) Copyright © 2017 Terms and Conditions

Figure 2 Metabolic Regulation of Small RNA Biogenesis and Function The mechanisms linking cellular metabolism to the abundance or the biological activity of individual RNA species differ according to the class of small RNA in question, although certain mechanisms (e.g., transcriptional regulation of small RNA precursor levels) are shared across the various small RNA classes. (A) Metabolic signaling can affect levels of small RNAs in the same way that it impacts chromatin or cytosine methylation (Figure 1), by altering levels of key small RNA biogenesis factors (SBFs) either transcriptionally or post-transcriptionally. In addition to global control of the biogenesis machinery, metabolic signaling can affect transcription of specific small RNA precursors (right panel). (B) As with chromatin- and DNA-modifying enzymes, RNA-modifying enzymes also utilize central metabolites as substrates and cofactors. As a result, alterations in metabolite levels can affect RNA modifications, potentially affecting small RNA biogenesis (shown are potential effects on tRNA cleavage or pri-miRNA processing) or even modification-dependent small RNA functions. (C) In the specific case of piRNAs, biogenesis occurs in close association with mitochondria—piRNA precursors are processed by Zucchini/MitoPLD at the outer membrane of mitochondria, for example—and thus any metabolic signaling to mitochondria could potentially affect assembly and function of nuage. (D) In the specific case of tRNAs, covalent “charging” of tRNAs with amino acids is sensitive to cellular amino acid levels, and alterations in tRNA charging could potentially affect tRNA processing to tRFs. SBF, small RNA biogenesis factor; AA, amino acid; SAM, S-adenosyl methionine; a-KG, α-ketoglutarate. Cell Metabolism 2017 25, 544-558DOI: (10.1016/j.cmet.2017.02.003) Copyright © 2017 Terms and Conditions