Biology subjects

Eichele, G.

Publications and source records attributed to Eichele, G..

3 recordsLinked to original sources

bioRxiv2021

Postnatal SETD1B is essential for learning and the regulation of neuronal plasticity genes

Histone 3 lysine 4 methylation (H3K4me) is mediated by six different lysine methyltransferases. Amongst these enzymes SET domain containing 1b (SETD1B) has been linked to syndromic intellectual disability but its role in the postnatal brain has not been studied yet. Here we employ mice that lack Setd1b from excitatory neurons of the postnatal forebrain and combine neuron-specific ChIP-seq and RNA-seq approaches to elucidate its role in neuronal gene expression. We observe that SETD1B controls the expression of genes with a broad H3K4me3 peak at their promoters that represent neuronal enriched genes linked to learning and memory function. Comparative analysis to corresponding data from conditional Kmt2a and Kmt2b knockout mice suggests that this function is specific to SETD1B. Moreover, postnatal loss of Setd1b leads to severe learning impairment, suggesting that SETD1B-mediated regulation of H3K4me levels in postnatal neurons is critical for cognitive function.

neuroscience↗

bioRxiv2020

Melanopsin-dependent direct photic effects are equal to clock-driven effects in shaping the nychthemeral sleep-wake cycle

Nychthemeral sleep-wake cycles (SWc) are known to be generated by the circadian clock in suprachiasmatic nuclei (SCN), entrained to the light-dark cycle. Light also exerts direct acute effects on sleep and waking. However, under longer photic exposure such as the 24-hour day, the precise significance of sustained direct light effects (SDLE) and circuitry involved have been neither clarified nor quantified, as disentangling them from circadian influence is difficult. Recording sleep in mice lacking a circadian pacemaker and/or melanopsin-based phototransduction, we uncovered, contrary to prevailing assumptions, that circadian-driven input shapes only half of SWc, with SDLE being equally important. SDLE were primarily mediated (>80%) through melanopsin, of which half were relayed through SCN, independent of clock function. These findings were used for a model that predicted SWc under simulated jet-lag, and revealed SDLE as a crucial mechanism influencing behavior, and should be considered for circadian/sleep disorder management and societal lighting optimization.

neuroscience↗

bioRxiv2019

Alternative catalytic residues in the active site of Esco acetyltransferases

Cohesin is a protein complex encircles the DNA and regulates the separation of sister chromatids during cell division. Following a catalytic mechanism that is insufficiently understood, Esco1 and Esco2 acetyltransferases acetylate Smc3 subunit of cohesin, thereby inducing a stabilization of cohesin on DNA. As a prerequisite for structure-guided investigation of enzymatic activity, we determine here the crystal structure of the mouse Esco2/CoA complex at 1.8 [A] resolution. We reconstitute the entire cohesin as a tetrameric assembly and use it as a physiologically-relevant substrate for enzymatic assays in vitro. Furthermore, we employ cell-based complementation studies in mouse embryonic fibroblast deficient for Esco1 and Esco2, as a means to identify catalytically-important residues in vivo. These analyses demonstrate that D567/S566 and E491/S527, located on opposite sides of the MmEsco2 active site cleft, are critical for catalysis. Our experiments supports a catalytic mechanism of acetylation where residues D567 and E491 are general bases that deprotonate the {varepsilon}-amino group of lysine substrate, via two nearby serine residues - S566 and S527-that possess a proton relay function.

molecular biology↗