UniProt functional annotation for P42568



	UniProt functional annotation for P42568

UniProt code: P42568.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: 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 (PubMed:20159561, PubMed:20471948, PubMed:25417107, PubMed:27105114, PubMed:27545619). Specifically recognizes and binds acylated histone H3, with a preference for histone H3 that is crotonylated (PubMed:25417107, PubMed:27105114, PubMed:27545619, PubMed:30374167, PubMed:30385749). Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors (PubMed:25417107, PubMed:27105114, PubMed:27545619). Recognizes and binds histone H3 crotonylated at 'Lys-9' (H3K9cr), and with slightly lower affinity histone H3 crotonylated at 'Lys-18' (H3K18cr) (PubMed:27105114). Also recognizes and binds histone H3 acetylated and butyrylated at 'Lys-9' (H3K9ac and H3K9bu, respectively), but with lower affinity than crotonylated histone H3 (PubMed:25417107, PubMed:27105114, PubMed:30385749). In the SEC complex, MLLT3 is required to recruit the complex to crotonylated histones (PubMed:27105114, PubMed:27545619). Recruitment of the SEC complex to crotonylated histones promotes recruitment of DOT1L on active chromatin to deposit histone H3 'Lys-79' methylation (H3K79me) (PubMed:25417107). Plays a key role in hematopoietic stem cell (HSC) maintenance by preserving, rather than confering, HSC stemness (PubMed:31776511). Acts by binding to the transcription start site of active genes in HSCs and sustaining level of H3K79me2, probably by recruiting DOT1L (PubMed:31776511). {ECO:0000269|PubMed:20159561, ECO:0000269|PubMed:20471948, ECO:0000269|PubMed:25417107, ECO:0000269|PubMed:27105114, ECO:0000269|PubMed:27545619, ECO:0000269|PubMed:30374167, ECO:0000269|PubMed:30385749, ECO:0000269|PubMed:31776511}.

Activity regulation: Crotonylated lysine binding is strongly inhibited by the peptide XL-07i, carrying a 2-furancarbonyl side chain and capped with a hydrophobic carboxybenzyl group (PubMed:30374167). XL-07i targets the unique pi-pi-pi stacking interaction at the crotonylation recognition site (PubMed:30374167). {ECO:0000269|PubMed:30374167}.

Subunit: Component of the super elongation complex (SEC), at least composed of EAF1, EAF2, CDK9, MLLT3/AF9, AFF (AFF1 or AFF4), the P-TEFb complex and ELL (ELL, ELL2 or ELL3) (PubMed:20159561, PubMed:20471948, PubMed:22195968, PubMed:23260655, PubMed:25417107). Interacts with BCOR (PubMed:10898795). Interacts with CBX8 (PubMed:11313972). Interacts with ALKBH4 (PubMed:23145062). {ECO:0000269|PubMed:10898795, ECO:0000269|PubMed:11313972, ECO:0000269|PubMed:20159561, ECO:0000269|PubMed:20471948, ECO:0000269|PubMed:22195968, ECO:0000269|PubMed:23145062, ECO:0000269|PubMed:23260655, ECO:0000269|PubMed:25417107}.

Subcellular location: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00376, ECO:0000269|PubMed:27105114}. Chromosome {ECO:0000269|PubMed:25417107, ECO:0000269|PubMed:27105114}. Note=Colocalizes with acylated histone H3 (PubMed:25417107, PubMed:27105114). Colocalizes with histone H3 crotonylated at 'Lys-18' (H3K18cr) (PubMed:27105114). {ECO:0000269|PubMed:25417107, ECO:0000269|PubMed:27105114}.

Tissue specificity: Enriched in undifferentiated hematopoietic stem cells in fetal liver, cord blood and bone marrow. {ECO:0000269|PubMed:31776511}.

Domain: The YEATS domain specifically recognizes and binds acylated histones, with a marked preference for histones that are crotonylated (PubMed:27105114, PubMed:27545619). Also binds histone H3 acetylated at 'Lys-9' (H3K9ac), but with lower affinity (PubMed:25417107, PubMed:27105114). Binds crotonylated lysine through a non-canonical pi- pi-pi stacking mechanism (PubMed:30374167, PubMed:30385749). The YEATS domain also binds DNA (PubMed:30385749). {ECO:0000269|PubMed:25417107, ECO:0000269|PubMed:27105114, ECO:0000269|PubMed:27545619, ECO:0000269|PubMed:30374167, ECO:0000269|PubMed:30385749}.

Disease: Note=A chromosomal aberration involving MLLT3 is associated with acute leukemias. Translocation t(9;11)(p22;q23) with KMT2A/MLL1. The result is a rogue activator protein. Fusion protein KMT2A-MLLT3 interacts with MEN1 and PSIP1 (PubMed:22936661, PubMed:25305204). {ECO:0000269|PubMed:10861294, ECO:0000269|PubMed:22936661, ECO:0000269|PubMed:25305204, ECO:0000269|PubMed:8506309}.

Disease: Note=A chromosomal aberration involving MLLT3 was observed in a patient with neuromotor development delay, cerebellar ataxia and epilepsy. Translocation t(4;9)(q35;p22). {ECO:0000269|PubMed:16001262}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		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 (PubMed:20159561, PubMed:20471948, PubMed:25417107, PubMed:27105114, PubMed:27545619). Specifically recognizes and binds acylated histone H3, with a preference for histone H3 that is crotonylated (PubMed:25417107, PubMed:27105114, PubMed:27545619, PubMed:30374167, PubMed:30385749). Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors (PubMed:25417107, PubMed:27105114, PubMed:27545619). Recognizes and binds histone H3 crotonylated at 'Lys-9' (H3K9cr), and with slightly lower affinity histone H3 crotonylated at 'Lys-18' (H3K18cr) (PubMed:27105114). Also recognizes and binds histone H3 acetylated and butyrylated at 'Lys-9' (H3K9ac and H3K9bu, respectively), but with lower affinity than crotonylated histone H3 (PubMed:25417107, PubMed:27105114, PubMed:30385749). In the SEC complex, MLLT3 is required to recruit the complex to crotonylated histones (PubMed:27105114, PubMed:27545619). Recruitment of the SEC complex to crotonylated histones promotes recruitment of DOT1L on active chromatin to deposit histone H3 'Lys-79' methylation (H3K79me) (PubMed:25417107). Plays a key role in hematopoietic stem cell (HSC) maintenance by preserving, rather than confering, HSC stemness (PubMed:31776511). Acts by binding to the transcription start site of active genes in HSCs and sustaining level of H3K79me2, probably by recruiting DOT1L (PubMed:31776511). {ECO:0000269\|PubMed:20159561, ECO:0000269\|PubMed:20471948, ECO:0000269\|PubMed:25417107, ECO:0000269\|PubMed:27105114, ECO:0000269\|PubMed:27545619, ECO:0000269\|PubMed:30374167, ECO:0000269\|PubMed:30385749, ECO:0000269\|PubMed:31776511}.


Activity regulation:		Crotonylated lysine binding is strongly inhibited by the peptide XL-07i, carrying a 2-furancarbonyl side chain and capped with a hydrophobic carboxybenzyl group (PubMed:30374167). XL-07i targets the unique pi-pi-pi stacking interaction at the crotonylation recognition site (PubMed:30374167). {ECO:0000269\|PubMed:30374167}.
Subunit:		Component of the super elongation complex (SEC), at least composed of EAF1, EAF2, CDK9, MLLT3/AF9, AFF (AFF1 or AFF4), the P-TEFb complex and ELL (ELL, ELL2 or ELL3) (PubMed:20159561, PubMed:20471948, PubMed:22195968, PubMed:23260655, PubMed:25417107). Interacts with BCOR (PubMed:10898795). Interacts with CBX8 (PubMed:11313972). Interacts with ALKBH4 (PubMed:23145062). {ECO:0000269\|PubMed:10898795, ECO:0000269\|PubMed:11313972, ECO:0000269\|PubMed:20159561, ECO:0000269\|PubMed:20471948, ECO:0000269\|PubMed:22195968, ECO:0000269\|PubMed:23145062, ECO:0000269\|PubMed:23260655, ECO:0000269\|PubMed:25417107}.
Subcellular location:		Nucleus {ECO:0000255\|PROSITE-ProRule:PRU00376, ECO:0000269\|PubMed:27105114}. Chromosome {ECO:0000269\|PubMed:25417107, ECO:0000269\|PubMed:27105114}. Note=Colocalizes with acylated histone H3 (PubMed:25417107, PubMed:27105114). Colocalizes with histone H3 crotonylated at 'Lys-18' (H3K18cr) (PubMed:27105114). {ECO:0000269\|PubMed:25417107, ECO:0000269\|PubMed:27105114}.
Tissue specificity:		Enriched in undifferentiated hematopoietic stem cells in fetal liver, cord blood and bone marrow. {ECO:0000269\|PubMed:31776511}.
Domain:		The YEATS domain specifically recognizes and binds acylated histones, with a marked preference for histones that are crotonylated (PubMed:27105114, PubMed:27545619). Also binds histone H3 acetylated at 'Lys-9' (H3K9ac), but with lower affinity (PubMed:25417107, PubMed:27105114). Binds crotonylated lysine through a non-canonical pi- pi-pi stacking mechanism (PubMed:30374167, PubMed:30385749). The YEATS domain also binds DNA (PubMed:30385749). {ECO:0000269\|PubMed:25417107, ECO:0000269\|PubMed:27105114, ECO:0000269\|PubMed:27545619, ECO:0000269\|PubMed:30374167, ECO:0000269\|PubMed:30385749}.
Disease:		Note=A chromosomal aberration involving MLLT3 is associated with acute leukemias. Translocation t(9;11)(p22;q23) with KMT2A/MLL1. The result is a rogue activator protein. Fusion protein KMT2A-MLLT3 interacts with MEN1 and PSIP1 (PubMed:22936661, PubMed:25305204). {ECO:0000269\|PubMed:10861294, ECO:0000269\|PubMed:22936661, ECO:0000269\|PubMed:25305204, ECO:0000269\|PubMed:8506309}.
Disease:		Note=A chromosomal aberration involving MLLT3 was observed in a patient with neuromotor development delay, cerebellar ataxia and epilepsy. Translocation t(4;9)(q35;p22). {ECO:0000269\|PubMed:16001262}.