Biology subjects

Ahmed, N. I.

Publications and source records attributed to Ahmed, N. I..

4 recordsLinked to original sources

bioRxiv2026

KMT2E recruitment by H3 serotonylation regulates neurodevelopmental chromatin dynamics

Histone H3 Gln 5 serotonylation (H3Q5ser) is a recently identified epigenetic modification in brain that modulates reader interactions with adjacent H3 Lys 4 trimethylation (H3K4me3) to promote transcriptional permissiveness. However, whether H3K4me3Q5ser and its associated binding proteins regulate neurodevelopmental gene expression programs remains unknown. Here, we identified the catalytically inactive Lysine methyltransferase 2E (KMT2E) as a reader of combinatorial H3K4me3Q5ser. KMT2E preferentially binds H3K4me3Q5ser over H3K4me3 alone, and enriches at broad chromatin domains marking actively transcribed neurodevelopmental loci. Notably, heterozygous variants in KMT2E have been implicated in ODLURO syndrome, a recently characterized neurodevelopmental disorder (NDD). To identify the molecular mechanisms underlying ODLURO syndrome, we generated a Kmt2e transgenic mouse model that reproduces behavioral, physiological, and cellular endophenotypes associated with this and other NDDs. Furthermore, we observed that KMT2E mediates these effects by recruiting the NCoR/HDAC3 repressor complex to H3K4me3Q5ser-marked loci to restrict spreading of co-localized H3 Lys 9 acetylation (H3K9ac). Inhibition of aberrant H3K9ac spreading was sufficient to rescue transcriptional dysregulation in Kmt2e haploinsufficient neurons. These findings thus establish KMT2E as a critical reader of H3 serotonylation during neurodevelopment and provide mechanistic insights into the pathogenesis of ODLURO syndrome.

neuroscience↗

bioRxiv2026

Incorporating motor preparation time transforms micro-offline gains into micro-offline losses

During explicit sequence learning (ESL), micro-offline gains (MOGS) occur during brief rest periods. MOGS are calculated as the difference in keypresses-per-second (KPS) between the first sequence of one trial and the last sequence of the preceding trial. To date, all studies evaluating MOGS have calculated KPS from the motor execution time (MET) that occurs between keypresses, but this approach ignores potential contributions from motor preparation which occur prior to the first keypress. Given that ESL relies on both pre-movement motor planning and subsequent motor execution, we hypothesized that ignoring motor preparation time (MPT) neglects a critical component of skill acquisition, potentially misrepresenting the true magnitude of MOGS. To test this, we calculated MOGS with and without MPT in thirty adults who performed an ESL task. Our results show that including MPT flipped MOGS from positive to negative and significantly increased the positive correlation between early learning and a gold-standard ESL metric: the number of correct sequences performed. Our results suggest that MPT should be incorporated into MOGS calculations and that excluding it overestimates micro-offline learning.

neuroscience↗

bioRxiv2023

Compensation between FOXP transcription factors maintains proper striatal function

Spiny projection neurons (SPNs) of the striatum are critical in integrating neurochemical information to coordinate motor and reward-based behavior. Mutations in the regulatory transcription factors expressed in SPNs can result in neurodevelopmental disorders (NDDs). Paralogous transcription factors Foxp1 and Foxp2, which are both expressed in the dopamine receptor 1 (D1) expressing SPNs, are known to have variants implicated in NDDs. Utilizing mice with a D1-SPN specific loss of Foxp1, Foxp2, or both and a combination of behavior, electrophysiology, and cell-type specific genomic analysis, loss of both genes results in impaired motor and social behavior as well as increased firing of the D1-SPNs. Differential gene expression analysis implicates genes involved in autism risk, electrophysiological properties, and neuronal development and function. Viral mediated re-expression of Foxp1 into the double knockouts was sufficient to restore electrophysiological and behavioral deficits. These data indicate complementary roles between Foxp1 and Foxp2 in the D1-SPNs.

neuroscience↗

bioRxiv2017

Forward Genetic ENU Mutagenesis Screen for Mouse Models of Chronic Fatigue Identifies a Novel Mutation in Slc2a4 (GLUT4)

In a screen of voluntary wheel-running behavior designed to identify genetic mouse models of chronic fatigue in ENU mutagenized C57BL/6J mice, we discovered two lines that showed aberrant wheel-running patterns. These lines both stem from a single original founder identified as a low body-weight candidate in a recessive screen. Progeny from both of these lines showed the abnormal wheel-running behavior, with affected mice showing significantly lower daily activity levels than unaffected mice. They also exhibited low amplitude circadian rhythms, consisting of lower activity levels during the normal active phase, and increased levels of activity during the rest or light phase, but only a modest alteration in free-running period. Their activity is not consolidated into longer bouts, but is frequently interrupted with periods of inactivity throughout the dark phase of the light-dark (LD) cycle. As seen with the low body weight, expression of the behavioral phenotypes in offspring of strategic crosses was consistent with a recessive heritance pattern. Mapping of these phenotypic abnormalities showed linkage to a single locus on chromosome 11, and whole exome sequencing (WES) identified a single point mutation in the Slc2a4 gene encoding the GLUT4 insulin-responsive glucose transporter. The single nucleotide change (A to T) was found in the distal end of exon 10, and results in a premature stop (Y440*). To our knowledge, this is the first time a mutation in this gene has been shown to result in extensive changes in general behavioral patterns.\n\nSIGNIFICANCE STATEMENTChronic fatigue is a debilitating and devastating disorder with widespread consequences for both the patient and the persons around them, but effective treatment strategies are lacking. The identification of novel genetic mouse models of chronic fatigue may prove invaluable for the study of its underlying physiological mechanisms and for the testing of treatments and interventions. A novel mutation in Slc2a4 (GLUT4) was identified in a forward mutagenesis screen because affected mice showed abnormal daily patterns and levels of wheel running consistent with chronic fatigue. This new mouse model may shed light on the pathophysiology of chronic fatigue.

genetics↗