| 2001 |
MACROH2A2 is a second macroH2A gene on human chromosome 10, encoding a protein with 68% amino acid identity to macroH2A1.2. It lacks the leucine zipper motif present in macroH2A1. By immunofluorescence, MACROH2A2 localizes to the inactive X chromosome in female cell nuclei, forming a Macro Chromatin Body co-localizing with macroH2A1. |
Gene cloning, sequence analysis, immunofluorescence on mouse tissue sections |
The Journal of biological chemistry |
High |
11262398
|
| 2001 |
MacroH2A2, like macroH2A1, forms a Macro Chromatin Body coincident with an X chromosome in female nuclei and co-localizes with macroH2A1 on the inactive X chromosome. Unlike macroH2A1, macroH2A2 maps to a different chromosomal locus (consistent with chromosome 10). |
Immunofluorescence with epitope-tagged constructs, co-localization with macroH2A1 antibody |
Human molecular genetics |
High |
11331621
|
| 2009 |
MacroH2A1 and macroH2A2, together, occupy promoters of key developmental and cell fate regulator genes in human male pluripotent cells, acting as a repressive mark that overlaps with Polycomb repressive complex 2 (PRC2/H3K27me3). Knockdown of macroH2A2 in zebrafish embryos produces severe developmental phenotypes, demonstrating a functional role in vertebrate development. |
Microarray-based chromatin occupancy analysis, co-occupancy with PRC2, morpholino knockdown in zebrafish |
Nature structural & molecular biology |
High |
19734898
|
| 2013 |
MacroH2A2 is the predominant barrier to somatic cell reprogramming to induced pluripotency among macroH2A isoforms. MacroH2A1 and macroH2A2 co-occupy pluripotency genes together with H3K27me3 in wild-type fibroblasts, particularly at target genes of the H3K27me3 demethylase UTX, which are reactivated early in iPS reprogramming. Loss of both macroH2A isoforms (dKO) in differentiated cells reduces the epigenetic barrier, allowing more efficient reprogramming. |
macroH2A double-knockout mouse fibroblasts, iPS reprogramming assays, ChIP-seq for macroH2A1/2 and H3K27me3, isoform rescue experiments |
Nature communications |
High |
23463008
|
| 2014 |
MacroH2A1 and macroH2A2 knockout mice show impaired prenatal and postnatal growth and reduced reproductive efficiency. MacroH2A2-containing nucleosomes substantially overlap in distribution with macroH2A1 and their effects on gene expression can be synergistic or opposing. In adult liver, macroH2A isoforms preferentially regulate lipid metabolism genes including the leptin receptor. |
Double knockout mouse model, gene expression profiling in fetal and adult liver, nucleosome distribution analysis |
Molecular and cellular biology |
High |
25312643
|
| 2014 |
MacroH2A2 exhibits dynamic exchange at gene promoters in embryonic stem cells (particularly highly transcribed genes), while large intergenic blocks of macroH2A2 are stably associated. Upon differentiation to fibroblasts, macroH2A2 is gained in additional stable blocks in gene-poor regions and turnover at promoters is dampened. |
Pulse-chase genome-wide histone dynamics (SNAP-tag pulse labeling) in murine ES cells and somatic tissues |
PLoS genetics |
Medium |
25102063
|
| 2014 |
Plcγ1 signaling downstream of Epo receptor activates macroH2A2 (H2afy2) expression, and macroH2A2 is a downstream effector of Plcγ1 required for erythroid maturation. Knockdown of macroH2A2 recapitulates the defect in erythroid differentiation caused by Plcγ1 inactivation. |
shRNA knockdown of Plcγ1 and macroH2A2 in erythroid progenitors, colony-forming assays, transcriptomics/DNA methylation analysis |
Cell death and differentiation |
Medium |
25394487
|
| 2018 |
The crystal structure of the macrodomain of human macroH2A2 at 1.7 Å resolution reveals that its putative binding pocket exhibits marked structural differences compared with macroH2A1.1, rendering macroH2A2 unable to bind ADP-ribose. Quantitative binding assays confirm this specificity is conserved across vertebrate macroH2A isoforms. The unstructured linker region (common to all macroH2A proteins) exerts a repressive effect on PARP1-dependent chromatin relaxation upon DNA damage. The macroH2A linker alone is sufficient to rescue heterochromatin architecture in macroH2A-deficient cells. |
Crystal structure at 1.7 Å, quantitative ADP-ribose binding assays, live-cell PARP1 activity assays, domain swap/deletion experiments in cells |
EMBO reports |
High |
30177554
|
| 2018 |
Active transcription defines the boundary of macroH2A2 chromatin domains via a 'pruning' mechanism: macroH2A2 is first broadly deposited genome-wide but is subsequently removed from actively transcribed regions by the FACT complex (facilitates chromatin transcription). Chemical inhibition of transcription counteracts pruning. Locus-specific gene activation depletes pre-existing macroH2A2, while gene silencing triggers ectopic macroH2A2 accumulation. |
Temporal genomic profiling (ChIP-seq) in macroH2A-null fibroblasts reconstituted with macroH2A2, chemical transcription inhibition, locus-specific transcriptional manipulation, FACT complex depletion |
Nature structural & molecular biology |
High |
30291361
|
| 2020 |
LSH (chromatin remodeling protein) specifically induces macroH2A2 deposition into chromatin in an ATP-dependent manner. LSH-mediated macroH2A2 deposition is required for transcriptional repression at target loci. ICF4 syndrome mutations in LSH fail to induce macroH2A2 deposition, and ICF4 patient cells display reduced macroH2A2 enrichment and transcriptional reactivation. |
Chemical-induced proximity (CIP) tethering of LSH to engineered locus, ChIP-seq for macroH2A, siRNA knockdown of macroH2A, ICF4 patient cell analysis, ATP-dependence assay |
Nature communications |
High |
33159050
|
| 2022 |
Inducible overexpression of macroH2A2 in vivo suppresses metastasis by enforcing a reversible growth arrest of disseminated cancer cells (dormancy). This dormancy program inhibits cell cycle and oncogenic signaling programs while up-regulating dormancy and senescence-associated inflammatory cytokines, and does not require dormancy-regulating transcription factors DEC2 or NR2F1. |
In vivo PDX models with inducible macroH2A2 expression, transcriptomic analysis, in vivo metastasis assays, DEC2/NR2F1 loss-of-function |
Science advances |
Medium |
36459552
|
| 2022 |
MacroH2A1.2 and macroH2A2 modulate enhancer-promoter contact frequency and enhancer activity in hepatoblastoma cells. Their removal affects NF-κB-mediated transcriptional responses to TNFα (facilitating the response) and suppresses response to IFN-γ. MacroH2A2 has a stronger contribution to gene repression than macroH2A1.2. |
Knockout of macroH2A1.2 and macroH2A2 in hepatoblastoma cells, Hi-C/chromatin conformation analysis, transcriptomic response to cytokines |
Cell reports |
Medium |
35732123
|
| 2023 |
MacroH2A2 shapes chromatin accessibility at enhancer elements to antagonize transcriptional programs of self-renewal in glioblastoma. MacroH2A2 also sensitizes cells to small molecule-mediated cell death via activation of a viral mimicry response. These findings are based on patient-derived in vitro and in vivo glioblastoma models. |
ATAC-seq for chromatin accessibility, transcriptomic profiling, patient-derived xenograft in vivo models, loss-of-function studies |
Nature communications |
Medium |
37244935
|
| 2023 |
MacroH2A2 marks a subset of inactive enhancers (macro-bound enhancers) lacking H3K27ac in a cell type-specific manner, maintaining cell identity. MacroH2A2 acts as a negative regulator of BRD4 chromatin occupancy at these enhancers. MacroH2A deficiency in mammary stem cells facilitates increased activity of transcription factors associated with stem cell activity. |
ChIP-seq for macroH2A and H3K27ac, BRD4 occupancy assays, single-cell ATAC-seq in mouse mammary stem cells, loss-of-function |
Communications biology |
Medium |
36823213
|
| 2024 |
MacroH2A1, but not macroH2A2, regulates the number of replication foci and DNA loop sizes (replicons) on the inactive X chromosome by interacting with the replicative helicase (MCM complex). This interaction is mediated by a phenylalanine residue in macroH2A1 that is not conserved in macroH2A2, and maps to the C-terminus of Mcm3. MacroH2A2-containing nucleosomes slow replication progression rate on the Xi (shared with macroH2A1), but macroH2A2 does NOT regulate helicase loading. |
Knockdown/knockout of individual macroH2A isoforms, replication focus imaging, DNA fiber assays, Co-IP of macroH2A1 with MCM helicase, domain mutagenesis (phenylalanine substitution) |
Nucleic acids research |
High |
39189450
|
| 2024 |
MacroH2A2 suppresses breast cancer malignancy by repressing TM4SF1 expression. The mH2A2/TM4SF1 axis controls the AKT/NF-κB signaling pathway; macroH2A2 knockdown activates AKT/NF-κB and increases MMP13 expression and secretion. Overexpression of macroH2A2 reduced tumor growth and lung metastasis in vivo. |
Knockdown/overexpression of macroH2A2 in breast cancer cells, microarray gene expression, TM4SF1 rescue experiments, in vivo tumor and metastasis models, AKT/NF-κB pathway analysis |
Molecular carcinogenesis |
Medium |
38251858
|