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"Collins, Kathleen"
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Multi-omic single-cell velocity models epigenome–transcriptome interactions and improves cell fate prediction
Multi-omic single-cell datasets, in which multiple molecular modalities are profiled within the same cell, offer an opportunity to understand the temporal relationship between epigenome and transcriptome. To realize this potential, we developed MultiVelo, a differential equation model of gene expression that extends the RNA velocity framework to incorporate epigenomic data. MultiVelo uses a probabilistic latent variable model to estimate the switch time and rate parameters of chromatin accessibility and gene expression and improves the accuracy of cell fate prediction compared to velocity estimates from RNA only. Application to multi-omic single-cell datasets from brain, skin and blood cells reveals two distinct classes of genes distinguished by whether chromatin closes before or after transcription ceases. We also find four types of cell states: two states in which epigenome and transcriptome are coupled and two distinct decoupled states. Finally, we identify time lags between transcription factor expression and binding site accessibility and between disease-associated SNP accessibility and expression of the linked genes. MultiVelo is available on PyPI, Bioconda and GitHub (
https://github.com/welch-lab/MultiVelo
).
MultiVelo extends the concept of RNA velocity to multimodal single-cell measurements.
Journal Article
Control of telomerase action at human telomeres
Telomerase recruitment and activity are regulated by telomere-bound proteins that protect the chromosome ends. In this Perspective, the authors discuss recent advances in understanding how the interactions of shelterin and telomerase components contribute to telomere-length homeostasis.
Recent progress has greatly increased the understanding of telomere-bound shelterin proteins and the telomerase holoenzyme, predominantly as separate complexes. Pioneering studies have begun to investigate the requirements for shelterin-telomerase interaction. From this vantage point, focusing on human cells, we review and discuss models for how telomerase and shelterin subunits coordinate to achieve balanced telomere-length homeostasis.
Journal Article
Qualitative analysis techniques for the review of the literature
In this article, we provide a framework for analyzing and interpreting sources that inform a literature review or, as it is more aptly called, a research synthesis. Specifically, using Leech and Onwuegbuzie's (2007, 2008) frameworks, we delineate how the following four major source types inform research syntheses: talk, observations, drawings/photographs/videos, and documents. We identify 17 qualitative data analysis techniques that are optimal for analyzing one or more of these source types. Further, we outline the role that the following five qualitative data analysis techniques can play in the research synthesis: constant comparison analysis, domain analysis, taxonomic analysis, componential analysis, and theme analysis. We contend that our framework represents a first step in an attempt to help literature reviewers analyze and interpret literature in an optimally rigorous way. Keywords: Review of the Literature, Research Synthesis, Qualitative Analysis, Constant Comparison Analysis, Domain Analysis, Taxonomic Analysis, Componential Analysis, Theme Analysis
Journal Article
HIV-1 Accessory Proteins Adapt Cellular Adaptors to Facilitate Immune Evasion
HIV-1 Vif, Vpu, and Vpr Adapt Cellular Ubiquitin Ligase Adaptors to Counteract Host Antiviral Responses Ubiquitination is a post-translational protein modification that regulates protein degradation and trafficking.\\n Recent studies have expanded the role of BST-2 to include viral sensing and signal transduction to activate NF-κB-dependent pro-inflammatory signals (reviewed in [23]). [...]the precise role of UNG2 remains controversial as it has both positive and negative effects on HIV-1 replication (reviewed in [26]). Because the interaction with UNG2 does not appear to explain all of Vpr's activities, it is likely that Vpr targets additional cellular proteins that have not yet been identified.
Journal Article
Vpr Promotes Macrophage-Dependent HIV-1 Infection of CD4+ T Lymphocytes
Vpr is a conserved primate lentiviral protein that promotes infection of T lymphocytes in vivo by an unknown mechanism. Here we demonstrate that Vpr and its cellular co-factor, DCAF1, are necessary for efficient cell-to-cell spread of HIV-1 from macrophages to CD4+ T lymphocytes when there is inadequate cell-free virus to support direct T lymphocyte infection. Remarkably, Vpr functioned to counteract a macrophage-specific intrinsic antiviral pathway that targeted Env-containing virions to LAMP1+ lysosomal compartments. This restriction of Env also impaired virological synapses formed through interactions between HIV-1 Env on infected macrophages and CD4 on T lymphocytes. Treatment of infected macrophages with exogenous interferon-alpha induced virion degradation and blocked synapse formation, overcoming the effects of Vpr. These results provide a mechanism that helps explain the in vivo requirement for Vpr and suggests that a macrophage-dependent stage of HIV-1 infection drives the evolutionary conservation of Vpr.
Journal Article
Cryo-EM structure of substrate-bound human telomerase holoenzyme
The enzyme telomerase adds telomeric repeats to chromosome ends to balance the loss of telomeres during genome replication. Telomerase regulation has been implicated in cancer, other human diseases, and ageing, but progress towards clinical manipulation of telomerase has been hampered by the lack of structural data. Here we present the cryo-electron microscopy structure of the substrate-bound human telomerase holoenzyme at subnanometre resolution, showing two flexibly RNA-tethered lobes: the catalytic core with telomerase reverse transcriptase (TERT) and conserved motifs of telomerase RNA (hTR), and an H/ACA ribonucleoprotein (RNP). In the catalytic core, RNA encircles TERT, adopting a well-ordered tertiary structure with surprisingly limited protein–RNA interactions. The H/ACA RNP lobe comprises two sets of heterotetrameric H/ACA proteins and one Cajal body protein, TCAB1, representing a pioneering structure of a large eukaryotic family of ribosome and spliceosome biogenesis factors. Our findings provide a structural framework for understanding human telomerase disease mutations and represent an important step towards telomerase-related clinical therapeutics.
A cryo-electron microscopy structure of the substrate-bound human telomerase holoenzyme, which lengthens the protective caps on chromosomes.
Journal Article
CD4 is expressed on a heterogeneous subset of hematopoietic progenitors, which persistently harbor CXCR4 and CCR5-tropic HIV proviral genomes in vivo
Latent HIV infection of long-lived cells is a barrier to viral clearance. Hematopoietic stem and progenitor cells are a heterogeneous population of cells, some of which are long-lived. CXCR4-tropic HIVs infect a broad range of HSPC subtypes, including hematopoietic stem cells, which are multi-potent and long-lived. However, CCR5-tropic HIV infection is limited to more differentiated progenitor cells with life spans that are less well understood. Consistent with emerging data that restricted progenitor cells can be long-lived, we detected persistent HIV in restricted HSPC populations from optimally treated people. Further, genotypic and phenotypic analysis of amplified env alleles from donor samples indicated that both CXCR4- and CCR5-tropic viruses persisted in HSPCs. RNA profiling confirmed expression of HIV receptor RNA in a pattern that was consistent with in vitro and in vivo results. In addition, we characterized a CD4high HSPC sub-population that was preferentially targeted by a variety of CXCR4- and CCR5-tropic HIVs in vitro. Finally, we present strong evidence that HIV proviral genomes of both tropisms can be transmitted to CD4-negative daughter cells of multiple lineages in vivo. In some cases, the transmitted proviral genomes contained signature deletions that inactivated the virus, eliminating the possibility that coincidental infection explains the results. These data support a model in which both stem and non-stem cell progenitors serve as persistent reservoirs for CXCR4- and CCR5-tropic HIV proviral genomes that can be passed to daughter cells.
Journal Article
Unboxing Difference: Cultivating Inclusive Literacy Classrooms Informed by Disability Studies
Inclusive literacy classrooms not only welcome diverse minds, bodies, cultures, and ways of making meaning into the instructional space but are deliberately, consciously, and strategically designed so that every teacher and learner in that space can access and participate in the physical, discursive, and intellectual work of the learning community. Here, Collins discusses how Disability Studies could help cultivate such classrooms.
Journal Article