## 2 Results and Discussion
### Discussion
In addition to the ELLs, the SEC contains the MLL translocation partners AF4/FMR2 family member 1 (AFF1; also known as AF4), AFF4, eleven-nineteen leukemia (ENL) and ALL1-fused gene from chromosome 9 (AF9) [47]. In this complex, ENL is linked, not only with all members of the AF4 protein family that occur as MLL fusion partners, but also with pTEFb and DOT1L [51,52]. Notably, several frequent MLL fusion partners seem to coordinate DOT1L activity with a protein complex that stimulates the elongation phase of transcription by phosphorylating the carboxy-terminal repeat domain of RNA polymerase II [49,50]. H3K79 me2 modification is tightly associated with active transcription [32, 33]. [PERSON] _et al._ speculated that conversion of monomethylated H3K79 into di- and trimethylated forms is correlated with the transition from low to high level gene transcription, due most likely to a decrease in the rate of transcription. Figure 6: Model for the regulation of alternative splicing of _Imp_ pre-mRNA by H3K79 me2 and DOT1L. (**A**) In males, a transcription elongation factor (X) promotes the formation of SEC on _Imp_, causing H3K79 methylation by DOT1L. Higher RNAP II processivity due to H3K79 me2 accumulation does not allow enough time to complete 3’-end processing at the proximal poly(A) site (AAGAAA), leading to exclusive use of the distal 3’ splice site of exon 8 and the distal poly(A) site (AAUAAA). While the distal poly(A) signal sequence is perfectly matched to the most canonical poly(A) signal hexamer, the proximal poly(A) signal sequence is consistent with a single-nucleotide variant of the canonical hexamer. Therefore, the polyaden methylation machinery prefers the distal poly(A) site rather than the proximal poly(A) site when both poly(A) sites are present on the nascent transcript simultaneously. The protein product from the male-specific _Imp_ transcript induces the male-specific splicing of _Bmdsx_ pre-mRNA; (**B**) In females, the presence of a dominant feminizing factor, _Fem_, on the W chromosome directly or indirectly represses the expression of X, leading to failure of SEC formation. Decreased accumulation of H3K79 me2 caused by the loss of SEC slows RNAP II processivity, providing sufficient time to recruit cleavage factors for 3’-end processing at the proximal poly(A) site. The absence of the male-specific Imp induces the female-specific splicing of _Bmdsx_ pre-mRNA. histone-DNA interaction [53]. Because H3K79 resides within the histone core, its methylation may facilitate DNA unwinding from the histone, allowing the downstream chromatin to open more readily and be transcribed more efficiently. Based on these previous findings, we propose a possible model for the regulatory mechanism underlying sex-specific alternative splicing of _Imp_ pre-mRNA (Figure 6). In male cells, exclusive expression of a transcription elongation factor (X), such as ELL family proteins, promotes the formation of SEC on _Imp_, causing H3K79 methylation by DOT1L. Higher RNAP II processivity due to H3K79 me2 accumulation does not allow enough time to complete 3'-end processing at the proximal, non-sex-specific poly(A) site, leading to exclusive use of the 3' splice site of exon 8. The male-specific Imp protein induces the male-specific splicing of _Bmdsx_ pre-mRNA (Figure 6A). We have found recently that male-specific Imp bound immediately downstream of the proximal poly(A) site and promoted male-specific splicing of its pre-mRNA [28]. Therefore, after the male-specific Imp protein has been produced, the protein product may inhibit use of the proximal poly(A) site and promote the splicing of intron 7, leading to exclusive use of the 3' splice site of exon 8. In female cells, _Fem_ directly or indirectly represses the expression of X, leading to failure of SEC formation. Decreased accumulation of H3K79 me2 caused by the loss of SEC slows RNAP II processivity, providing sufficient time to recruit cleavage factors such as CF I, CF II, and/or poly(A) polymerase (PAP) for 3'-end processing at the proximal poly(A) site.