I am absolutely humbled and honored to have been selected as a new HHMI Investigator. A huge shout-out to all of my brilliant lab members (past and present), outstanding collaborators and incredible mentors along the way who made this a possibility!!.

many amazing collaborators, without whom, none of this would have been possible. Hope you all enjoy!.

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But I couldn’t be more excited to finally have this work published. Also, a huge thanks to our incredibly helpful Editor, Dr. Ted Dobie, and our insightful Reviewers at Neuron, who truly demonstrated what scientific review should look like. Finally, a huge thanks to our.

This project, which robustly identifies a novel astrocytic regulator of Major-depressive-disorder associated stress susceptibility represents a monumental effort by one of the most talented young scientists that I have ever known. Sasha will follow up with summaries of the work.

So incredibly excited to be able to officially highlight the outstanding work of @SashaLFulton, a previous superstar PhD student in my lab and now a superstar postdoc in the @IshmailSaboor lab at Columbia (also an @HHMINEWS Hanna H. Gray Fellow), now out at @NeuroCellPress !!.

RT @SinaiBrain: .@SinaiBrain & @IcahnMountSinai congratulate @EricJNestler for his election to @theNASciences of the USA. This great honor….

RT @SinaiBrain: How do the brain & body communicate w/ each other? Our thoughts & emotions often feel in sync w/ physical sensations in ou….

RT @HHMINEWS: Today we're thrilled to announce our 2024 #HannaGrayFellows! Please join us in welcoming and celebrating these outstanding ea….

It was such a pleasure collaborating with you on this project, Qingfei! As they say, team work makes the dream work, and what an outstanding team this was 😎 here’s to many more!.

And here is the beautifully written News & Views on our new paper from @debo_Astrocyte and Tatiana Kutateladze. Thank you both!.

Massive thanks to all authors, including @QZ_ChemSynBiol @BenjaminWeekley @DavidVinson93 @RyanBastle Shuai Zhao and many many more on getting this across the finish line!.

Using a viral approach to disrupt H3 monoaminylations in TMN, we significantly ablated circadian gene expression in this region. This matched behavioral phenotypes indicating significantly disrupted circadian entrainment in mice.

Through analysis, we show WDR5 binding is primarily at CLOCK/BMAL1 target genes, and binding was severely diminished at ZT20 when H3Q5his enrichment is high & H3Q5ser is low. This matches work showing MLL1 & CLOCK physically interact [Paulo Sassone-Corsi’s group (PMID 21113167)].

There was a high correlation between rhythmic gene expression and rhythmic H3Q5his levels, with levels peaking during the mouse’s active phase (ZT16/ZT20). These genes were significantly enriched with motifs for CLOCK, one of the master regulators of circadian gene expression.

RNA-seq revealed cyclic gene expression in mouse TMN over zeitgeber time (ZT), a 24 hour diurnal period. Correlating with this, we observed cycling of H3Q5his, H3Q5ser, & WDR5 genomic enrichment across ZT (measured every 4 hours) in TMN using spike-in CUT&RUN-seq.

Histamine in brain is primarily made in the tuberomammillary nucleus (TMN), which projects to multiple brain regions. When probing H3Q5his levels across multiple regions, we found H3Q5his was highest in TMN, which has been implicated in controlling sleep/wake cycles & alertness.

Via X-ray crystallography of the H3Q5his-WDR5 WD40 complex, we identified a key residue (K259) in proximity to the + charged histamine that leads to inhibited binding. Mutating WDR5 K259-to-A259 led to a reversal of antagonism by H3Q5his, and increased gene expression in cells.

This is in contrast to H3Q5ser, which previously was found to increase binding of WDR5 (and we corroborated this), leading to increased activity of MLL/SETD1 complexes in vitro and in cellulo (PMID 34144982).

Mechanistically, we found that H3Q5his antagonizes binding of the H3 tail ‘reader,’ WDR5, which is a core member of mammalian H3K4 methyltransferase complexes. H3Q5his greatly disrupts the binding of WDR5, and thus the activity of MLL/SETD1 complexes in vitro.

Surprisingly, we found that TG2 not only acts as the ‘writer’ of histone monoaminylations, but also as the ‘eraser’ and ‘exchanger’ of monoamines on H3Q5. This is a highly unconventional chromatin-based mechanism, which based on our findings can occur rapidly in vivo.

Previously, we discovered that histone H3 can be modified (at H3Q5) by monoamine neurotransmitters, such as serotonin and dopamine. Here, we identify that histamine (his) can also be added at H3Q5. These monoamines are deposited by the enzyme transglutaminase 2 (TG2).