- Spatiotemporal Epigenetic Control of the Histone Gene Chromatin Landscape during the Cell Cycle(PubMed)
Author : Andrew J Fritz 1, Prachi N Ghule 1, Rabail Toor 1, Louis Dillac 1, Jonah Perelman 2, Joseph Boyd 3, Jane B Lian 4, Johnathan A R Gordon 1, Seth Frietze 5, Andre Van Wijnen 2, Janet L Stein 6, Gary S Stein 6
Abstract : Higher-order genomic organization supports the activation of histone genes in response to cell cycle regulatory cues that epigenetically mediates stringent control of transcription at the G1/S-phase transition. Histone locus bodies (HLBs) are dynamic, non-membranous, phase-separated nuclear domains where the regulatory machinery for histone gene expression is organized and assembled to support spatiotemporal epigenetic control of histone genes. HLBs provide molecular hubs that support synthesis and processing of DNA replication-dependent histone mRNAs. These regulatory microenvironments support long-range genomic interactions among non-contiguous histone genes within a single topologically associating domain (TAD). HLBs respond to activation of the cyclin E/CDK2/NPAT/HINFP pathway at the G1/S transition. HINFP and its coactivator NPAT form a complex within HLBs that controls histone mRNA transcription to support histone protein synthesis and packaging of newly replicated DNA. Loss of HINFP compromises H4 gene expression and chromatin formation, which may result in DNA damage and impede cell cycle progression. HLBs provide a paradigm for higher-order genomic organization of a subnuclear domain that executes an obligatory cell cycle-controlled function in response to cyclin E/CDK2 signaling. Understanding the coordinately and spatiotemporally organized regulatory programs in focally defined nuclear domains provides insight into molecular infrastructure for responsiveness to cell signaling pathways that mediate biological control of growth, differentiation phenotype, and are compromised in cancer.
2.Spatiotemporal Control of Articulation During Speech and Speechlike Tasks in Amyotrophic Lateral Sclerosis (PubMed)
Abstract : Purpose This study examined the articulatory control of speech and speechlike tasks in individuals with amyotrophic lateral sclerosis (ALS) and neurologically healthy individuals with the aim to identify the most useful set of articulatory features and tasks for assessing bulbar motor involvement in ALS. Method Tongue and jaw kinematics were recorded in 12 individuals with bulbar ALS and 10 healthy controls during a speech task and two speechlike tasks (i.e., alternating motion rate [AMR], sequential motion rate [SMR]). Eight articulatory features were derived for each participant per task, including the range, maximum speed, and acceleration time of tongue and jaw movements as well as the coupling and timing between tongue and jaw movements. The effects of task (i.e., AMR, SMR, speech) and group (i.e., ALS, control) on these articulatory features were evaluated. For each feature, the task that yielded the largest difference between the ALS and control groups was identified. The diagnostic efficacy of these task-specific features was assessed using the receiver operating characteristic analysis; the relation of these task-specific features to a well-established bulbar severity index-speaking rate-was determined using Spearman’s rank correlation. Results Seven task-specific articulatory features were identified, including (a) tongue and jaw acceleration time during the AMR task, (b) tongue-jaw coupling during the SMR task, and © range of tongue movement, maximum tongue and jaw speed, and temporal lag between tongue and jaw movements during the speech task. Among these features, tongue and jaw acceleration time and their temporal lag showed relatively high accuracy (i.e., 0.83–0.95) in differentiating individuals with ALS from healthy controls. Range of tongue movement and maximum tongue and jaw speed showed significant correlations with speaking rate. Conclusion Findings provided preliminary evidence for the utility of task-specific articulatory measurements as a novel quantitative assessment to detect and predict bulbar motor involvement in ALS.