Biomedical subjects

Anthony J Hannan

Publications and source records attributed to Anthony J Hannan.

3 recordsLinked to original sources

PubMed2026

A modular class-aware workflow for small RNA sequencing analysis using mouse sperm as a case study.

BACKGROUND: Small RNA sequencing analysis is challenging because RNA classes differ in biogenesis, sequence redundancy, genomic organization, and annotation reliability. Integrated workflows accommodating these constraints remain limited, particularly for fragment-level and cluster-level analysis. METHODS: We present a reproducible, containerized, class-aware workflow for small RNA sequencing analysis, using mouse sperm as a case study. The workflow combines standardized preprocessing with complementary annotation and quantification strategies for microRNAs (miRNAs), transfer RNA-derived small RNAs (tsRNAs), ribosomal RNA-derived small RNAs (rsRNAs), and PIWI-interacting RNA (piRNA)-enriched genomic clusters. Using sperm small RNA data from offspring of lipopolysaccharide (LPS)-exposed male mice, we compared integrated-reference mapping, multi-class annotation, fragment-level tsRNA profiling, and genome-based piRNA cluster analysis, with custom modules for locus-aware harmonization and condition-specific cluster analysis. RESULTS: Integrated-reference mapping aligned 88.17% of reads and retained 690 features after filtering. It identified 11 differentially expressed miRNAs between LPS and controls, while other classes showed limited signal. Fragment-level profiling improved tsRNA resolution. piRNA cluster analysis identified 958 control and 940 LPS clusters, with 18 control-specific and no LPS-specific clusters. CONCLUSION: This workflow supports transparent, reproducible, class-aware interpretation of small RNA sequencing data while emphasizing cautious interpretation of piRNA-enriched signals from total small RNA sequencing.

Small non-coding RNA analysis↗

PubMed2024

Convergence on CaMK4: A Key Modulator of Autism-Associated Signaling Pathways in Neurons.

Although the precise underlying cause(s) of autism spectrum disorder remain unclear, more than 1000 rare genetic variations are associated with the condition. For many people living with profound autism, this genetic heterogeneity has impeded the identification of common biological targets for therapy development for core and comorbid traits that include significant impairments in social communication and repetitive and restricted behaviors. A substantial number of genes associated with autism encode proteins involved in signal transduction and synaptic transmission that are critical for brain development and function. CAMK4 is an emerging risk gene for autism spectrum disorder that encodes the CaMK4 (calcium/calmodulin-dependent protein kinase 4) enzyme. CaMK4 is a key component of a Ca2+-activated signaling pathway that regulates neurodevelopment and synaptic plasticity. In this review, we discuss 3 genetic variants of CAMK4 found in individuals with hyperkinetic movement disorder and comorbid neurological symptoms including autism spectrum disorder that are likely pathogenic with monogenic effect. We also comment on 4 other genetic variations in CAMK4 that show associations with autism spectrum disorder, as well as 12 examples of autism-associated variations in other genes that impact CaMK4 signaling pathways. Finally, we highlight 3 environmental risk factors that impact CaMK4 signaling based on studies of preclinical models of autism and/or clinical cohorts. Overall, we review molecular, genetic, physiological, and environmental evidence that suggest that defects in the CaMK4 signaling pathway may play an important role in a common autism pathogenesis network across numerous patient groups, and we propose CaMK4 as a potential therapeutic target.

Humans↗

PubMed2024

Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice.

Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally, coupled with the inherent reversibility of chromatin modifications, may afford an opportunity for therapeutic intervention following a genetic diagnosis. Development of treatments requires an understanding of protein function and models of the disease. Here, we provide a mouse model of Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736) and demonstrate proof-of-principle efficacy of postnatal treatment. SBBYSS results from heterozygous mutations in the KAT6B (MYST4/MORF/QFK) gene and is characterized by intellectual disability and autism-like behaviors. Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b+/-), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation. Kat6b+/- mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals. Treatment with a histone deacetylase inhibitor, valproic acid, or an acetyl donor, acetyl-carnitine (ALCAR), elevated histone acetylation levels in the human cells with SBBYSS mutations and in brain and blood cells of Kat6b+/- mice and partially reversed gene expression changes in Kat6b+/- cortical neurons. Both compounds improved sociability in Kat6b+/- mice, and ALCAR treatment restored learning and memory. These data suggest that a subset of SBBYSS individuals may benefit from postnatal therapeutic interventions.

Animals↗