Zinc Metalloproteins in Epigenetics and Their Crosstalk

Abstract

More than half a century ago, zinc was established as an essential micronutrient for normal human physiology. In silico data suggest that about 10% of the human proteome potentially binds zinc. Many proteins with zinc-binding domains (ZBDs) are involved in epigenetic modifications such as DNA methylation and histone modifications, which regulate transcription in physiological and pathological conditions. Zinc metalloproteins in epigenetics are mainly zinc metalloenzymes and zinc finger proteins (ZFPs), which are classified into writers, erasers, readers, editors, and feeders. Altogether, these classes of proteins engage in crosstalk that fundamentally maintains the epigenome's modus operandi. Changes in the expression or function of these proteins induced by zinc deficiency or loss of function mutations in their ZBDs may lead to aberrant epigenetic reprogramming, which may worsen the risk of non-communicable chronic diseases. This review attempts to address zinc's role and its proteins in natural epigenetic programming and artificial reprogramming and briefly discusses how the ZBDs in these proteins interact with the chromatin.

Keywords: epigenetics; epigenome; zinc finger domain; zinc finger motif; zinc finger proteins; zinc metalloproteins.

Figure 1

Comparison between de novo DNA methylation and maintenance DNA methylation. The figure compares de novo DNA methylation and maintenance DNA methylation. The two forms of DNA methylation catalyzed by DNMTs. (A) = unmethylated DNA; (B) = hemimethylated DNA; (C) and (D) = fully methylated DNA; DNMT3a/DNMT3b = DNA methyltransferases 3a/3b, both catalyze de novo DNA methylation (methylation of a newly formed double-stranded DNA during gametogenesis and embryogenesis). DNMT1 = DNA methyltransferase 1: It catalyzes replication-dependent maintenance of DNA methylation existing on hemimethylated DNA. Red dots stand for methyl groups. Source: Icons were obtained and customized in BioRender (biorender.com (accessed on 23 February 2021)).

Figure 2

Role of zinc in DNA and histone methylation through the folate-mediated one-carbon metabolism. This figure summarizes the pathways linking one-carbon metabolism with DNA and histone methylation. Zinc-dependent enzymes and key intermediates are highlighted in different colors. BHMT (orange) = Betaine homocysteine methyltransferase: A zinc-dependent enzyme, which catalyzes the alternate reaction of methionine synthesis; DMG = Dimethylglycine; DNMTS (dark green) = DNA methyltransferases: Catalyze DNA methylation and have zinc-binding domains that regulate their activities; HMTs (dark green) = histone methyltransferases: Catalyze histone, lysine, and arginine methylation; MTR (pink) = Methionine synthase: It is zinc-dependent and catalyzes the direct synthesis of methionine (the direct precursor of SAM) from homocysteine and N⁵-methyl THF; SAH = S-Adenosylhomocysteine; SAM (light green) = S-Adenosylmethionine: The activated methyl donor for methylation reactions; THF = Tetrahydrofolate: The active form of folate that supplies methyl groups to homocysteine to form methionine. Zn2+ (red) = Zinc ion. Source: Image was created in Corel Draw X3 Graphics Suite (Pixmantec Rawshooter essentials 2005. Version 1.1.3).

Figure 3

Labeled cartoon representation of a Cys2His2 zinc finger motif. A C2H2 zinc finger is an essential structural component of fully methylated DNA reader proteins with methyl binding domains. The red dot represents the zinc atom; the spiral structure denotes the alpha-helix; the two antiparallel arrows are the beta-sheets. The two five-membered rings extending from the alpha helix are the imidazole rings of histidine; the two curves extending from the beta-sheets and pointing toward the red dot are the thiols of the two cysteine residues. Source: Icon was obtained and customized in BioRender (biorender.com (accessed on 23 February 2021)).

Figure 4

Cartoon representation of the zinc finger (ZF) array. A customized sequential array of six Cys2His2 ZFs: each of the six units containing a red dot surrounded by a coiled strand and two antiparallel arrows represent a Cys2His2 ZF. The red dot is the zinc ion coordinated by the side chains of two cysteines and two histidine residues. ZF arrays are employed in synthetic epigenetics to edit (add or delete) epigenetic marks at predetermined DNA or histone regions. They are usually coupled with writers or erasers to achieve this purpose. Source: Icons were obtained and customized in BioRender (biorender.com (accessed on 23 February 2021)).

Figure 5

Summary of zinc metalloproteins and their roles in epigenome regulation. Figure 5 summarizes the various classes of zinc metalloproteins that come together to regulate the epigenome. Writers, erasers, readers, editors, and feeders represent the names of the types. These classes of proteins work together in a coordinated manner to regulate the epigenome. Examples of enzymes/proteins in each category are given in abbreviations. BHMT = Betaine homocysteine methyltransferase: a zinc metalloenzyme that catalyzes the formation of methionine from homocysteine and betaine, an essential reaction in DNA and histone methylation; chromo = Chromodomain containing proteins such as heterochromatin protein 1 (HP1), an H3K9 methyl reader that facilitates heterochromatin condensation; C2H2 ZFs = 2-Cysteine-2-Histidine-type of zinc fingers, critical readers of fully methylated DNA; DNMTS = DNA methyltransferases, enzymes that catalyze de novo and maintenance DNA methylation at the CpG islands of fully methylated or hemimethylated DNA; HATs = Histone acetyltransferases, enzymes that catalyze histone lysine acetylation; HDACs = Histone deacetylases, enzymes that catalyze removal acetyl groups from acetyl-lysine residues of histone tails; HMTs = Histone methyltransferases, enzymes that catalyze the methylation of histones on lysine residues; KDMs = Histone lysine demethylases, enzymes that remove methyl groups from the methylated lysine residues of histones; MTR = Methionine synthase, an enzyme that catalyzes the synthesis of methionine from homocysteine and tetrahydrofolate, an essential reaction for DNA and histone acetylation; PHD = Plant homeodomain containing zinc finger proteins, they serve as versatile readers of histone modifications; SRA = SET and RING finger Associated domain-containing proteins: they read hemimethylated DNA. USP22 = Ubiquitin-specific protease 22: the catalytic component of the human deubiquitinating module complex that catalyzes histone deubiquitination. ZF MBPs = Zinc finger methyl binding proteins: readers of fully methylated DNA. Source: Image was created in BioRender (biorender.com (accessed on 23 February 2021)).