JASPer controls interphase histone H3S10 phosphorylation by chromosomal kinase JIL-1 in Drosophila

Abstract

31In flies, the chromosomal kinase JIL-1 is responsible for most interphase histone H3S10 32 phosphorylation and has been proposed to protect active chromatin from acquiring 33 heterochromatic marks, like dimethylated histone H3K9 (H3K9me2) and HP1. Here, we show 34 that JIL-1's targeting to chromatin depends on a new PWWP domain-containing protein 35JASPer (JIL-1 Anchoring and Stabilizing Protein). The JASPer-JIL-1 (JJ)-complex is the 36 major form of the kinase in vivo and is targeted to active genes and telomeric transposons 37 via binding of the PWWP domain of JASPer to H3K36me3 nucleosomes. Put in place, the 38 complex modulates the transcriptional output. JIL-1 and JJ-complex depletion in cycling cells 39 lead to small changes in H3K9me2 distribution at active genes and telomeric transposons. 40Finally, we identified many new interactors of the endogenous JJ-complex and propose that 41 JIL-1 not only prevents heterochromatin formation, but also coordinates chromatin-based 42 regulation in the transcribed part of the genome. 43 Key Words: PWWP domain / histone phosphorylation / COMPASS / heterochromatin / BOD1 44 / Dpy-30L1 / Telomeres 45 46 Main text 47In mammals, several nuclear kinases contribute to phosphorylation of histone H3 at serine 48 10 (H3S10ph) in interphase, whereas in Drosophila melanogaster, the essential kinase JIL-1 49 is responsible for most of it 1 . The significance of interphase H3S10ph is often 50 underestimated because most H3S10 phosphorylation in asynchronous cell populations 51 stems from mitotic chromatin, where it is deployed by Aurora kinase B 2,3 . Originally, 52interphase H3S10ph has been associated, in combination with H3K9ac and H3K14ac, with 53 transcriptional activation of immediate early genes upon MAPK activation 4,5 . In Drosophila, 54interphase H3S10ph is enriched at the body of active genes 6 . In mammal, in the extreme 55 case of mouse embryonic stem cells (mESC), ~30% of the genome is enriched for H3S10ph 56 in interphase 7 . 57The current model is that JIL-1 protects euchromatin from heterochromatization 8 . According 58 to the phospho-methyl switch model for mitotic H3S10ph 9 , placing H3S10ph prevents H3K9 59 methylation and subsequent binding of heterochromatin components. JIL-1 phosphorylates 60 various H3 peptides with different methylation states, including H3K9me2/3, with a 61 comparable efficiency 6 , whereas histone methyltransferases of the Su(var)3-9 family are 62 inhibited by H3S10ph 10,11 . Several observations suggest that JIL-1 is important for the 63 balance between eu-and heterochromatin. The Su(var)3-1 alleles of JIL-1 gene, which lead 64 to the expression of JIL-1 truncated in its C-terminal domain (CTD), result in reduced 65 heterochromatin spreading at euchromatin-heterochromatin boundaries 12,13 . Conversely, in 66 the JIL-1 z2/z2 null mutant, heterochromatin components spread into euchromatin. The 67 spreading of H3K9me2 and HP1 is highest on the euchromatic part of the X chromosome in 68 both sexes 14 , the spreading of the 7-zinc-finger pr...

How HP1 Post-Translational Modifications Regulate Heterochromatin Formation and Maintenance

“…H3S10ph also takes place in interphase, where it has been associated with transcription activation [ 29 , 30 , 31 ]. It is mediated by several kinases in mammals [ 32 ] but mostly by JIL-1 kinase in Drosophila [ 33 , 34 , 35 ]. H3S10ph allosterically inhibits the action of methyltransferases like G9A and Su(var)3-9 thus affecting HP1α recruitment [ 36 ].…”

A bioinformatics screen reveals Hox and chromatin remodeling factors at theDrosophilahistone locus

“…MSL1 and Ndf may target the histone gene array in other tissues or only in embryos, representing potential false negatives. However, JIL-1 is a more generalized kinase that is responsible for phosphorylating serine 10 in histone 3 across the genome, not just on the male X-chromosome (Regnard et al 2011;Cai et al 2014;Albig et al 2019). JIL-1 may therefore be present at the histone locus independent of its role in dosage compensation by contributing to the epigenetic landscape of the histone locus.…”

H3K36 methylation and DNA-binding both promote Ioc4 recruitment and Isw1b remodeller function

“…A number of PWWP domain-containing proteins have been identified in recent years. They are associated with a variety of protein (complexes) and involved in a diverse set of functions, such as DNA repair (24,40), transcriptional activation (41,42) and repression (3,22,43), DNA methyltransferases (12,44–46), histone lysine methyltransferases (47) and acetyltransferases (48–52) as well as limiting the spreading of heterochromatin (53,54). Many of these PWWP domains preferentially bind methylated histones, with particular emphasis on methylated H3K36 or H4K20 (3,15,43).…”