Macroh2a2 is a histone variant that belongs to the MACROH2A core histone family [5]. It has a unique hybrid structure with an amino-terminal domain similar to histone H2A followed by a large non-histone region. Macroh2a2 plays important roles in epigenetic regulation, influencing chromatin accessibility, transcriptional programs, and cell responses [1,2,4,7]. It is involved in pathways related to self-renewal, cell dormancy, and response to inflammatory cytokines, which are crucial for normal development and disease processes [1,2,7]. Genetic models, such as gene knockout mouse models, are valuable for studying its functions.

In glioblastoma, patient-derived in vitro and in vivo models show that Macroh2a2 shapes chromatin accessibility at enhancer elements to antagonize transcriptional programs of self-renewal, and also sensitizes cells to small molecule-mediated cell death via a viral mimicry response. High transcriptional levels of Macroh2a2 are associated with better prognosis of high-grade glioma patients [1].

In disseminated cancer cells, inducible expression of Macroh2a2 in vivo suppresses metastasis via a reversible growth arrest, by inhibiting cell cycle and oncogenic signaling programs, while up-regulating dormancy and senescence-associated inflammatory cytokines [2].

In anal neoplasm, loss of Macroh2a2 expression is associated with disease progression, and patients with Macroh2a2-negative lesions have earlier recurrence [3].

In colorectal cancer, deficiency of 15-LOX-1 induces radioresistance through down-regulation of Macroh2a2, and Macroh2a2 suppresses the DNA damage response in irradiated cells by delaying H2AX activation [6].

In hepatoblastoma cells, removal of Macroh2a2 affects the contact frequency of promoters and distal enhancers, coinciding with or preceding changes in enhancer activity in response to cytokines [7].

In conclusion, Macroh2a2 is an important epigenetic regulator involved in multiple biological processes and disease conditions. Model-based research, especially using KO mouse models, has revealed its roles in glioblastoma, cancer metastasis, anal neoplasm progression, radioresistance in colorectal cancer, and response to cytokines in cancer cells. Understanding the functions of Macroh2a2 provides insights into disease mechanisms and potential treatment strategies.