MACROH2A is a replacement for histone H2A that also supports heterochromatin formation. In particular, one subtype of MACROH2A, macroH2A1.2, is concentrated in the inactive X chromosome in adult females. In fact, in some mammals macroH2A1 appears to be the earliest marker of the inactive X chromosome and is the only change that has been shown to occur during the period when transcriptional silencing is initiated. It is proposed that the PRC1 complex is involved in the maintenance of X chromosome inactivation in somatic cells via regulation of methylation. MACROH2A deposition has been suggested to be regulated by the CULLIN3 - SPOP - RBX1 ligase complex and is actively involved in stable X inactivation, likely through the formation of an additional layer of epigenetic silencing. E3 ubiquitin ligase, consisting of SPOP and CULLIN3, is able to ubiquitinate the Polycomb group protein BMI1 and the variant histone MACROH2A. PRC1 is also recruited to the inactivated X chromosome in somatic cells in a highly dynamic, cell cycle-regulated manner. Recent study has indicated that knockdown of CULLIN3 or SPOP results in the loss of MACROH2A from the inactivated X chromosome, leading to reactivation even in the presence of methylation and deacetylase inhibitors. SPOP mutations have been implicated in endometrial cancer through the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. Thus, the PRC1 complex is involved in the maintenance of X chromosome inactivation in somatic cells. Another study has shown that alternative splicing of the histone variant MACROH2A1 regulates cancer cell proliferation via QKI splicing factor through RNA interference. MacroH2A1 splicing is perturbed in several types of cancer including lung cancer. The accumulating body of evidence demonstrates that changes in chromatin structure occur in oncogenesis, and changes in the expression of histone variants are beginning to be observed in cancer due to the changes in chromatin structure and function. Polycomb group proteins have been implicated in this path. EZH2, a histone-lysine N-methyltransferase and the functional enzymatic component of PRC2, encoded by the EZH2 gene, is a popular point of study in the treatment of B cell lymphoma.