Table 2.
Histone variants’ functions, alterations, and role in cancers. This table summarized all the 19 histone H2A variants’ primary and additional functions, alterations consequences and their role play in different cancer types.
| Variants’ Name | Primary Functions | Other Functions | Role and Alterations in Cancers |
|---|---|---|---|
| H2A.X | DNA damage repair | 1. Regulate and define mESCs proliferation 2. Immune response 3. Growth 4. Reproduction 5. Establishment of mESCs totipotency 6. Regulate fate of hPSCs and progenitor cells |
Alterations’ consequences P53−/− heterozygous loss: genome instability P53−/− homozygous loss: early cancer formation, impairment of DNA repair, growth retardation, immune deficient and infertility Mutations observed in sarcomas, brain tumor, neck squamous cell carcinoma, B and T cell lymphomas Alterations in phosphorylation site of H2A.X (Tyr39) Role in cancer: Tumor suppressor Regulate cancer progression and metastasis (breast, ovarian cancers, HCC, and CRC) |
| H2A.Z | Regulator of gene transcription | 1. DNA replication 2. DNA damage repair 3. Cell lineage differentiation 4. Chromosome aggregation 5. Neuronal development, cognitive function, memory processing |
Alterations’ consequences H2A.Z+/− heterozygous loss: embryonic lethality in high eukaryotes, cell cycle arrest Role in cancers: Oncogenic variants Regulate cell proliferation and metastasis (ER positive breast cancer, CRC, liver, lung, prostate, metastatic melanoma, PDAC and bladder) |
| H2A.Z.1 | Transcription initiation and elongation | Mouse early embryonic development |
Alterations’ consequences H2A.Z.1 KO: mouse early embryonic lethality, cell cycle arrest Role in cancers: Oncogenic variants Regulate tumorigenesis and metastasis (HCC and ICC) |
| H2A.Z.2 | Gene regulation | Regulate cell proliferation and apoptosis |
Alterations’ consequences H2A.Z.2 KO: Reduced cell proliferation but increase apoptosis, cell cycle arrest Role in cancers: Oncogenic variants Regulate cell proliferation and metastasis (aggressive melanoma, PDAC) |
| H2A.Z.2.2 | Destabilizing nucleosome | Unknown |
Alterations’ consequences H2A.Z.2.2 KO: Cell cycle arrest Role in cancers: Oncogenic variants Regulate cell proliferation and metastasis (PDAC) |
| MacroH2A1 | Maintainer of heterochromatin architecture | 1. Stabilizing XCI 2. Regulate memory processing and formation |
Role in cancers: Tumor suppressor Regulate cell proliferation, migration, and metastasis (melanoma, breast, liver, lung, bladder, cervical, ovarian cancers, and CRC) |
| MacroH2A2 | Maintainer of heterochromatin architecture and chromatin organization | 1. Stabilizing XCI 2. Reprogramming barrier in fully differentiated cells |
Role in cancers: Tumor suppressor Regulate cell proliferation, metastasis, and gene expressions |
| MacroH2A1.1 | Maintainer of heterochromatin architecture | 1. NAD+ metabolism 2. ADP-ribose signaling 3. DNA damage repair (NHEJ) |
Role in cancers: Tumor suppressor Regulate cancer metastasis and cell proliferation |
| MacroH2A1.2 | Maintainer of heterochromatin architecture | 1. Inhibit PARP-1 enzymatic activity 2. Mediating homologous repair (HR) |
Role in cancers: Tumor suppressor Regulate cell proliferation, inhibit cancers induced osteoclastogenesis |
| H2A.R | Spermatogenesis | Unknown | Unknown |
| H2A.Bbd | Transcriptional regulation | Controlling preimplantation embryonic development |
Role in cancers: Oncogenic variants Cells with shorter S phase, increased sensitivity to DNA damage Regulate gene transcription regulation and cell proliferation (HL, BLCA, UCEC, cervical squamous cell carcinomas and endocervical carcinoma) |
| H2A.P | Unknown | Unknown |
Role in cancers: Oncogenic variants (Unknown functions) |
| H2A.Q | Unknown | Unknown |
Role in cancers: Oncogenic variants (Unknown functions) |
| H2A.L | Unknown | Unknown |
Role in cancers: Oncogenic variants (Unknown functions) |
| H2A.L.2 | Spermatogenesis, male mouse fertility | Unknown |
Alterations’ consequences H2A.L.2 KO: complete mouse fertility Role in cancers: Oncogenic variants (Unknown functions) |
| H2A.L.3 | Unknown | Unknown | Unknown |
| H2A.22 (H2A.J) | Stimulate inflammatory signaling cascade during DNA damage | Tissues or organs specific functions regardless of aging |
Role in cancers: Oncogenic variants In luminal type B breast cancer, KIRC, aggressive melanoma, brain Role in cancers: Tumor suppressor In prostate, bladder cancers and all subtypes of breast cancer excluding luminal A Regulate gene expressions (ER positive breast cancer and prostate cancer) Mediate chemoradiotherapy resistance through signaling pathways (CRC, HCC, and glioblastoma) |
| H2A.1 | Spermatogenesis, iPSCs generation and early embryogenesis | Unknown |
Alterations’ consequences H2A.1 KD: perturbation in genome reprogramming Role in cancers: Oncogenic variants Regulate cell proliferation (HCC, CRC) |
| H2A.2 | Mice neurons differentiation, embryogenesis, and aging | Unknown |
Role in cancers Hyper-methylated in HCC (Unknown functions) Varying degree of PTMs |
Abbreviations: mESCs: mouse embryonic stem cells; HCC: hepatocellular carcinoma; CRC: Colorectal cancer; hPSCs: human Pluripotent Stem Cells; ER: estrogen receptor; PDAC: pancreatic ductal adenocarcinoma; KO: knockout; ICC: intrahepatic cholangiocarcinoma; XCI: X chromosome inactivation; NHEJ: non-homologous end joining; HR: homologous repair; HL: Hodgkin’s lymphoma; BLCA: urothelial bladder carcinomas; UCEC: Uterine Corpus Endometrial Carcinomas; PARP-1: Poly(ADP-ribose) Polymerase 1; KIRC: Kidney Renal Cell Carcinoma; KD: knockdown; iPSCs: Induce Pluripotent Stem Cells; PTMs: post-transcriptional modifications.