|Gene Name||H2AFY (H2A histone family member Y)|
|Protein|| H2AFY codes for the proteins MACROH2A1. The first exon is non-coding. Due to alternative exons 6 (coding exons 5), coding for amino acids (aa) 198-226 or 229, there are 2 isoforms. Isoform MacroH2A1.1: 369 aa; 39,1 kDa; Isoform MacroH2A1.2: 372 aa, 39,6 kDa; This protein comprises a histone H2A domain (aa: 2-117; length: 116 aa) with a HA2 signature: AGVIFPV (aa: 19-25), a Lys-rich region (aa: 118-162; length: 45 aa) with a SQ-motif (aa 139-140) which can be phosphorylated by PIKKs, and a macro domain (aa: 184-370; length: 187). Ubiquitination sites are at Lys115, Lys116 and Lys119 (Ogawa et al., 2005). Glycines (Gly224 and Gly314) are required for PAR (poly(ADP-ribose)) binding. |
MacroH2A1.1 is mainly found in differentiated, non-proliferative tissues, MacroH2A1.1 is upregulated in senescent cells; MacroH2A1.2 is more generally expressed, including in tissues with ongoing cell proliferation (Sporn and Jung 2012).
MACROH2A1 regulates gene transcription, DNA damage response, mitochondrial respiration and senescence.
Methylations/acetylations MacroH2A1 is found on autosomes as part of facultative heterochromatin and is localized at two functionally distinct chromatin subtypes marked by trimethylation of histone H3 on lysine 27 (H3K27me3) or as part of transcriptionally active euchromatin marked by nine histone acetylations (H2B at K15 and K20; H3 at K4, K14 and K18; H4 at K91; and H2A at K5) where it can either positively or negatively regulate transcription (reviewed in Ruiz and Gamble 2018).
MacroH2A1.1-PARP1 axis Stressing signals generated during DNA damage repair, senescence, hormonal response, heat shock, or differentiation promote the binding of MacroH2A1.1 to activated PARP1 (poly(ADP-ribose) polymerase 1), creating the macroH2A1.1-PARP1 axis. MacroH2A1.1 recruit active PARP1 to chromatin and promotes the CREBBP -mediated acetylation of H2B K12 and K120, which either positively or negatively regulates the expression of MacroH2A1-target genes. On the other hand, when MacroH2A1.1 is highly expressed, MacroH2A1.1 can bind and inhibit PARP1 activity Chen et al., 2014; Hurtado-Bagès et al., 2018).
MacroH2A1 regulates mitochondrial respiration MacroH2A1.1 reduces nuclear NAD+ consumption through PARP1 inhibition, allowing maintenance of mitochondrial NAD+ pools that are critical for respiration (Posavec Marjanovic et al., 2014).
Epithelial-mesenchymal transition MacroH2A1.1 isoform, but not MacroH2A1.2, can suppress EMT induction.
Cancer Upregulation of mH2A1 induces SKP2 subsequent CDK8 downregulation contributes to growth defect, G2/M arrest, polyploidy and tumour suppression in breast cancer (Xu et al., 2015). MacroH2A1.2, one of the MacroH2A isoforms (see above), has an intrinsic ability to inhibit breast cancer-derived osteoclastogenesis and prostate cancer-induced osteoclastogenesis. Overexpression of mH2A1.2, but not mH2A1.1, in breast cancer cells significantly increased ERBB2 expression and tumorigenicity (Li et al., 2012). Re-expression of MacroH2A1.1 suppressed cancer cell proliferation, anchorage-independent growth and cell invasiveness in breast cancer, and suppressed metastasis of melanoma through regulation of CDK8. Loss of MacroH2A1.1 was associated with cell growth and metastasis and a worse outcome in colon cancer. Conversely, MacroH2A1.2 levels have been found to be similar in all tumors independently of proliferation (Sporn and Jung 2012). Patients with low MacroH2A1.1 levels in lung tumor samples recur more likely. MacroH2A1 downregulation enhances the stem-like properties of bladder cancer cells. In contrast, in the claudin-low subtype of triple negative breast cancer ( ESR1 -, PGR -, normal ERBB2) presenting a high MacroH2A1.1 mRNA ratio exhibit a poor outcome , through epithelial-mesenchymal transition process towards metastatic development (Lavigne et al., 2014).
| Chen H, Ruiz PD, Novikov L, Casill AD, Park JW, Gamble MJ|
| 1 and PARP-1 cooperate to regulate transcription by promoting CBP-mediated H2B acetylation Nat Struct Mol Biol|
| H2AFY is a novel fusion partner of MECOM in acute myeloid leukemia|
| Han Q, Lu J, Wang J, Ye J, Jiang X, Chen H, Liu C, Chen L, Lin T, Chen S, Sun M, Gao F|
| Cancer Genet 2018 Apr;222-223:9-12|
| The MacroH2A1|
| Hurtado-Bagès S, Guberovic I, Buschbeck M|
| 1 - PARP1 Axis at the Intersection Between Stress Response and Metabolism Front Genet|
| Increased macroH2A1|
| Lavigne AC, Castells M, Mermet J, Kocanova S, Dalvai M, Bystricky K|
| 1 expression correlates with poor survival of triple-negative breast cancer patients PLoS One|
| The atypical histone macroH2A1|
| Li X, Kuang J, Shen Y, Majer MM, Nelson CC, Parsawar K, Heichman KA, Kuwada SK|
| 2 interacts with HER-2 protein in cancer cells J Biol Chem|
| Histone variant macroH2A1|
| Ogawa Y, Ono T, Wakata Y, Okawa K, Tagami H, Shibahara KI|
| 2 is mono-ubiquitinated at its histone domain Biochem Biophys Res Commun|
| Posavec Marjanović M, Hurtado-Bagès S, Lassi M, Valero V, Malinverni R, Delage H, Navarro M, Corujo D, Guberovic I, Douet J, Gama-Perez P, Garcia-Roves PM, Ahel I, Ladurner AG, Yanes O, Bouvet P, Suelves M, Teperino R, Pospisilik JA, Buschbeck M|
| 1 regulates mitochondrial respiration by limiting nuclear NAD(+) consumption Nat Struct Mol Biol|
| MacroH2A1 chromatin specification requires its docking domain and acetylation of H2B lysine 20|
| Ruiz PD, Gamble MJ|
| Nat Commun 2018 Dec 3;9(1):5143|
| Differential regulation and predictive potential of MacroH2A1 isoforms in colon cancer|
| Sporn JC, Jung B|
| Am J Pathol 2012 Jun;180(6):2516-26|
| Skp2-macroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis|
| Xu D, Li CF, Zhang X, Gong Z, Chan CH, Lee SW, Jin G, Rezaeian AH, Han F, Wang J, Yang WL, Feng ZZ, Chen W, Wu CY, Wang YJ, Chow LP, Zhu XF, Zeng YX, Lin HK|
| Nat Commun 2015 Mar 30;6:6641|
| de Braekeleer E, Douet-Guilbert, N, Le Bris MJ, Basink A, Morel F, de Braekeleer M.|
| Atlas Genet Cytogenet Oncol Haematol. 2013;17(7):491-493.|