Protein AF-9

Definition:

Chromatin reader component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. Specifically recognizes and binds acylated histone H3, with a preference for histone H3 that is crotonylated. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. Recognizes and binds histone H3 crotonylated at 'Lys-9' (H3K9cr), and with slightly lower affinity histone H3 crotonylated at 'Lys-18' (H3K18cr). Also recognizes and binds histone H3 acetylated and butyrylated at 'Lys-9' (H3K9ac and H3K9bu, respectively), but with lower affinity than crotonylated histone H3. In the SEC complex, MLLT3 is required to recruit the complex to crotonylated histones. Recruitment of the SEC complex to crotonylated histones promotes recruitment of DOT1L on active chromatin to deposit histone H3 'Lys-79' methylation (H3K79me). Plays a key role in hematopoietic stem cell (HSC) maintenance by preserving, rather than confering, HSC stemness. Acts by binding to the transcription start site of active genes in HSCs and sustaining level of H3K79me2, probably by recruiting DOT1L.

References:

[1]. Yuanyuan Li, et al. AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation. Cell. 2014 Oct 23;159(3):558-71. [Content Brief]

[2]. Vincenzo Calvanese, et al. MLLT3 governs human haematopoietic stem-cell self-renewal and engraftment. Nature. 2019 Dec;576(7786):281-286. [Content Brief]

[3]. Qiang Zhang, et al. Structural Insights into Histone Crotonyl-Lysine Recognition by the AF9 YEATS Domain. Structure. 2016 Sep 6;24(9):1606-12. [Content Brief]

[4]. Xin Li, et al. Structure-guided development of YEATS domain inhibitors by targeting π-π-π stacking. Nat Chem Biol. 2018 Dec;14(12):1140-1149. [Content Brief]

[5]. Yuanyuan Li, et al. Molecular Coupling of Histone Crotonylation and Active Transcription by AF9 YEATS Domain. Mol Cell. 2016 Apr 21;62(2):181-193. [Content Brief]

[6]. Brianna J Klein, et al. Structural insights into the π-π-π stacking mechanism and DNA-binding activity of the YEATS domain. Nat Commun. 2018 Nov 1;9(1):4574. [Content Brief]

[7]. Chengqi Lin, et al. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol Cell. 2010 Feb 12;37(3):429-37. [Content Brief]

[8]. Nanhai He, et al. HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol Cell. 2010 May 14;38(3):428-38. [Content Brief]

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