The super elongation complex (SEC) and MLL in development and disease

Abstract

Transcriptional regulation at the level of elongation is vital for the control of gene expression and metazoan development. The mixed lineage leukemia (MLL) protein and its Drosophila homolog, Trithorax, which exist within COMPASS (complex of proteins associated with Set1)-like complexes, are master regulators of development. They are required for proper homeotic gene expression, in part through methylation of histone H3 on Lys 4. In humans, the MLL gene is involved in a large number of chromosomal translocations that create chimeric proteins, fusing the N terminus of MLL to several proteins that share little sequence similarity. Several frequent translocation partners of MLL were found recently to coexist in a super elongation complex (SEC) that includes known transcription elongation factors such as eleven-nineteen lysine-rich leukemia (ELL) and P-TEFb. Importantly, the SEC is required for HOX gene expression in leukemic cells, suggesting that chromosomal translocations involving MLL could lead to the overexpression of HOX and other genes through the involvement of the SEC. Here, we review the normal developmental roles of MLL and the SEC, and how MLL fusion proteins can mediate leukemogenesis.

Bromodomain and Extra-terminal (BET) Bromodomain Inhibition Activate Transcription via Transient Release of Positive Transcription Elongation Factor b (P-TEFb) from 7SK Small Nuclear Ribonucleoprotein

“…Of note, this JQ1-and ELL2-dependent activation of HIV transcription occurred in the absence of Tat. We conclude and confirm that as with MLL fusion proteins MED26 and the polymerase-associated factor complex (20,31,32), the SEC can recruit P-TEFb to transcription units, in this case, to the HIV LTR.…”

“…Glycerol Gradients-Glycerol gradients (10 -30%) were established by pipetting 2 ml of each glycerol fraction (10,15,20,25, and 30%, v/v) in medium-salt buffer A into centrifugation tubes (Beckman 331372). Gradients were formed by standing for 6 h at 4°C.…”

“…It also increased transcription of HEXIM1 and its incorporation into the 7SK snRNP. Moreover, its effects on HIV transcription could be inhibited by depletion of ELL2, a subunit of the SEC (20).…”

HIV-1 Tat recruits transcription elongation factors dispersed along a flexible AFF4 scaffold

“…Potential dynamic variations in the composition of these complexes have been suggested for the HIV promoter (17). AFF1 also binds P-TEFb in vivo (25,42), and ENL and AF9 compete for scaffold binding (30). With four, three, and two human homologs of AFF4, ELL, and ENL, respectively, as well as posttranslational modifications of the subunits, including P-TEFb (14,43,44), these data demonstrate the potential for considerable variability in SEC composition.…”

“…These results suggest an inherent combinatorial multiplicity that may be modulated to allow greater functional diversity (42). Potential dynamic variations in the composition of these complexes have been suggested for the HIV promoter (17).…”