Biology subjects

Han, Z.

Publications and source records attributed to Han, Z..

5 recordsLinked to original sources

bioRxiv2018

Termination of non-coding transcription in yeast relies on both a CTD-interaction domain and a CTD-mimic in Sen1

Pervasive transcription is a widespread phenomenon leading to the production of a plethora of non-coding RNAs (ncRNAs) without apparent function. Pervasive transcription poses a risk that needs to be controlled to prevent the perturbation of gene expression. In yeast, the highly conserved helicase Sen1 restricts pervasive transcription by inducing termination of non-coding transcription. However, the mechanisms underlying the specific function of Sen1 at ncRNAs are poorly understood. Here we identify a motif in an intrinsically disordered region of Sen1 that mimics the phosphorylated carboxy terminal domain (CTD) of RNA polymerase II and characterize structurally its recognition by the CTD-interacting domain of Nrd1, an RNA-binding protein that binds specific sequences in ncRNAs. In addition, we show that Sen1-dependent termination strictly requires the recognition of the CTD by the N-terminal domain of Sen1. We provide evidence that the Sen1-CTD interaction does not promote Sen1 initial recruitment but rather the capacity of Sen1 to induce the release of paused RNAPII from the DNA. Our results shed light onto the network of protein-protein interactions that control termination of non-coding transcription by Sen1.

genetics↗

bioRxiv2018

Functional connectivity alterations of the temporal lobe and hippocampus in semantic dementia and Alzheimer’s disease

The severe semantic memory impairments in semantic dementia have been attributed to a pronounced atrophy and functional disruption of the anterior temporal lobes. In contrast, the medial and posterior temporal lobe damage predominantly found in patients with Alzheimers disease has been associated with episodic memory disturbance. However, the two dementia subtypes share hippocampal deterioration, despite a relatively spared episodic memory in semantic dementia. To gain more insight into the mutual and divergent functional alterations seen in Alzheimers disease and semantic dementia, we assessed the differences in intrinsic functional connectivity between temporal lobe regions in patients with Alzheimers disease (n = 16), semantic dementia patients from two international sites (n = 23), and healthy controls (n = 17). In an exploratory study, we used a functional parcellation of the temporal cortex to extract time series. The Alzheimers disease group showed a single connection with reduced functional connectivity as compared to the controls. This connection was located between the right orbitofrontal cortex and the right anterior temporal lobe. In contrast, functional connectivity was decreased in the semantic dementia group in six connections, mainly involving the hippocampus, lingual gyrus, temporal pole, and orbitofrontal cortex. We identified a common pathway with semantic dementia, since the functional connectivity between the right anterior temporal lobe and the right orbitofrontal cortex was reduced in both types of dementia. This might be related to social knowledge deficits as part of semantic memory decline. However, such interpretations are preferably made in the context of all disease-specific semantic impairments and functional connectivity changes. Despite some limitations owed to the two database sites, this study provides a first preliminary picture of the brains functional dysconnectivity in Alzheimers disease and semantic dementia. Future studies are needed to replicate findings of such a common pathway with matched diagnosis, neuropsychological, and data MRI acquisition procedures.

neuroscience↗

bioRxiv2018

High-throughput automatic training system for odor-based learned behaviors in head-fixed mice

Understanding neuronal mechanisms of cognitive behaviors requires efficient behavioral assays. We designed a high-throughput automatic training system (HATS) for olfactory behaviors in head-fixed mice. The hardware and software were constructed to enable automatic training with minimal human intervention. The integrated system was composed of customized 3D-printing supporting components, an odor-delivery unit with fast response, Arduino based hardware-controlling and data-acquisition unit. Furthermore, the customized software was designed to enable automatic training in all training phases, including lick-teaching, shaping, and learning. Using HATS, we trained mice to perform delayed non-match to sample (DNMS), delayed paired association (DPA), Go/No-go (GNG), and GNG reversal tasks. These tasks probed cognitive functions including sensory discrimination, working memory, decision making, and cognitive flexibility. Mice reached stable levels of performance within several days in the tasks. HATS enabled an experimenter to train eight mice simultaneously, therefore greatly enhanced the experimental efficiency. Combined with causal perturbation and activity recording techniques, HATS can greatly facilitate our understanding of the neural-circuitry mechanisms underlying cognitive behaviors.

neuroscience↗

bioRxiv2018

Targeted epigenomic changes to the maize methylome resulting from tissue culture

DNA methylation can contribute to the maintenance of genome integrity and regulation of gene expression. In most situations, DNA methylation patterns are inherited quite stably. However, changes in DNA methylation can occur at some loci as a result of tissue culture resulting in somaclonal variation. A sequence-capture bisulfite sequencing approach was implemented to monitor context-specific DNA methylation patterns in ~15Mb of the maize genome for a population of plants that had been regenerated from tissue culture. Plants that have been regenerated from tissue culture exhibit gains and losses of DNA methylation at a subset of genomic regions. There was evidence for a high rate of homozygous changes to DNA methylation levels that occur consistently in multiple independent tissue culture lines suggesting the existence of a targeted process for altering epigenetic state during tissue culture. The consistent changes induced by tissue culture include both gains and losses of DNA methylation and can affect CG, CHG or both contexts within a region. The majority of changes in DNA methylation exhibit stable inheritance although there is some evidence for stochastic reacquisition of the initial epigenetic state in some individuals. This study provides insights into the susceptibility of some loci and potential mechanisms that could contribute to altered DNA methylation and epigenetic state that occur during tissue culture in plant species.

plant biology↗

bioRxiv2017

Subtle perturbations of the maize methylome reveal genes and transposons silenced by DNA methylation

DNA methylation is a chromatin modification that can provide epigenetic regulation of gene and transposon expression. Plants utilize several pathways to establish and maintain DNA methylation in specific sequence contexts. The chromomethylase (CMT) genes maintain CHG (where H = A, C or T) methylation. The RNA-directed DNA methylation (RdDM) pathway is important for CHH methylation. Transcriptome analysis was performed in a collection of Zea mays lines carrying mutant alleles for CMT or RdDM-associated genes. While the majority of the transcriptome was not affected, we identified sets of genes and transposon families sensitive to context-specific decreases in DNA methylation in mutant lines. Many of the genes that are up-regulated in CMT mutant lines have high levels of CHG methylation, while genes that are differentially expressed in RdDM mutants are enriched for having nearby mCHH islands, providing evidence that context-specific DNA methylation directly regulates expression of a small number of genes. The analysis of a diverse set of inbred lines revealed that many genes regulated by CMTs exhibit natural variation for DNA methylation and gene expression. Transposon families with differential expression in the mutant genotypes show few defining features, though several families up-regulated in RdDM mutants show enriched expression in endosperm, highlighting the importance for this pathway during reproduction. Taken together, our findings suggest that while the number of genes and transposon families whose expression is reproducibly affected by mild perturbations in context-specific methylation is small, there are distinct patterns for loci impacted by RdDM and CMT mutants.

plant biology↗