The evolutionary history of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast to stable genetic events, epigenetic states are reversible and sensitive to ...the microenvironment, prompting the question whether epigenetic information can similarly be used to discover tumor phylogeny. We examined the spatial and temporal dynamics of DNA methylation in a cohort of low-grade gliomas and their patient-matched recurrences. Genes transcriptionally upregulated through promoter hypomethylation during malignant progression to high-grade glioblastoma were enriched in cell cycle function, evolving in parallel with genetic alterations that deregulate the G1/S cell cycle checkpoint. Moreover, phyloepigenetic relationships robustly recapitulated phylogenetic patterns inferred from somatic mutations. These findings highlight widespread co-dependency of genetic and epigenetic events throughout brain tumor evolution.
Display omitted
•Dramatic loss of DNA methylation during the progression of low-grade gliomas to GBM•Phenotypic convergence of genomic and epigenomic evolution on cell cycle defects•Phyloepigenetics recapitulates the phylogenetics of tumor evolution•Robust model of gliomagenesis from tumor initiation through malignant progression
Mazor et al. show that spatial and temporal patterns of DNA methylation and somatic mutations during the progression of low-grade gliomas to high-grade tumors produce remarkably similar evolutionary histories and both converge to deregulate the cell cycle.
Reactivation of telomerase reverse transcriptase (TERT) expression enables cells to overcome replicative senescence and escape apoptosis, which are fundamental steps in the initiation of human ...cancer. Multiple cancer types, including up to 83% of glioblastomas (GBMs), harbor highly recurrent TERT promoter mutations of unknown function but specific to two nucleotide positions. We identified the functional consequence of these mutations in GBMs to be recruitment of the multimeric GA-binding protein (GABP) transcription factor specifically to the mutant promoter. Allelic recruitment of GABP is consistently observed across four cancer types, highlighting a shared mechanism underlying TERT reactivation. Tandem flanking native E26 transformation-specific motifs critically cooperate with these mutations to activate TERT, probably by facilitating GABP heterotetramer binding. GABP thus directly links TERT promoter mutations to aberrant expression in multiple cancers.
The majority of common variants associated with common diseases, as well as an unknown proportion of causal mutations for rare diseases, fall in noncoding regions of the genome. Although catalogs of ...noncoding regulatory elements are steadily improving, we have a limited understanding of the functional effects of mutations within them. Here, we perform saturation mutagenesis in conjunction with massively parallel reporter assays on 20 disease-associated gene promoters and enhancers, generating functional measurements for over 30,000 single nucleotide substitutions and deletions. We find that the density of putative transcription factor binding sites varies widely between regulatory elements, as does the extent to which evolutionary conservation or integrative scores predict functional effects. These data provide a powerful resource for interpreting the pathogenicity of clinically observed mutations in these disease-associated regulatory elements, and comprise a rich dataset for the further development of algorithms that aim to predict the regulatory effects of noncoding mutations.
Telomerase (TERT) activation is a fundamental step in tumorigenesis. By maintaining telomere length, telomerase relieves a main barrier on cellular lifespan, enabling limitless proliferation driven ...by oncogenes. The recently discovered, highly recurrent mutations in the promoter of TERT are found in over 50 cancer types, and are the most common mutation in many cancers. Transcriptional activation of TERT, via promoter mutation or other mechanisms, is the rate-limiting step in production of active telomerase. Although TERT is expressed in stem cells, it is naturally silenced upon differentiation. Thus, the presence of TERT promoter mutations may shed light on whether a particular tumor arose from a stem cell or more differentiated cell type. It is becoming clear that TERT mutations occur early during cellular transformation, and activate the TERT promoter by recruiting transcription factors that do not normally regulate TERT gene expression. This review highlights the fundamental and widespread role of TERT promoter mutations in tumorigenesis, including recent progress on their mechanism of transcriptional activation. These somatic promoter mutations, along with germline variation in the TERT locus also appear to have significant value as biomarkers of patient outcome. Understanding the precise molecular mechanism of TERT activation by promoter mutation and germline variation may inspire novel cancer cell-specific targeted therapies for a large number of cancer patients.
Vascular dysfunction has a critical role in Alzheimer’s disease (AD). Recent data from brain imaging studies in humans and animal models suggest that cerebrovascular dysfunction may precede cognitive ...decline and onset of neurodegenerative changes in AD and AD models. Cerebral hypoperfusion and impaired amyloid β-peptide (Aβ) clearance across the blood–brain barrier (BBB) may contribute to the onset and progression of dementia AD type. Decreased cerebral blood flow (CBF) negatively affects the synthesis of proteins required for memory and learning, and may eventually lead to neuritic injury and neuronal death. Impaired clearance of Aβ from the brain by the cells of the neurovascular unit may lead to its accumulation on blood vessels and in brain parenchyma. The accumulation of Aβ on the cerebral blood vessels, known as cerebral amyloid angiopathy (CAA), is associated with cognitive decline and is one of the hallmarks of AD pathology. CAA can severely disrupt the integrity of the blood vessel wall resulting in micro or macro intracerebral bleedings that exacerbates neurodegenerative process and inflammatory response and may lead to hemorrhagic stroke, respectively. Here, we review the role of the neurovascular unit and molecular mechanisms in vascular cells behind AD and CAA pathogenesis. First, we discuss apparent vascular changes, including the cerebral hypoperfusion and vascular degeneration that contribute to different stages of the disease process in AD individuals. We next discuss the role of the low-density lipoprotein receptor related protein-1 (LRP), a key Aβ clearance receptor at the BBB and along the cerebrovascular system, whose expression is suppressed early in AD. We also discuss how brain-derived apolipoprotein E isoforms may influence Aβ clearance across the BBB. We then review the role of two interacting transcription factors, myocardin and serum response factor, in cerebral vascular cells in controlling CBF responses and LRP-mediated Aβ clearance. Finally, we discuss the role of microglia and perivascular macrophages in Aβ clearance from the brain. The data reviewed here support an essential role of neurovascular and BBB mechanisms in contributing to both, onset and progression of AD.
To synthesize experimental research on the impact of narrative point of view (POV) on message processing and persuasion outcomes in health promotion. Moderators examined included characteristics of ...study design, participants, and experimental stimuli.
Random effects model meta-analysis of 16 health promotion experiments, using the metafor package in R. Studies included compared the effects of first- and third-person POV on risk perceptions, attitudes, behavioral intention, identification and transportation.
There was no evidence of publication bias. Narratives told in the first-person POV led to higher levels of perceived susceptibility (d = 0.10, 95% CI 0.01, 0.20) and identification feelings (d = 0.10, 95% CI 0.10, 0.21) than third-person narratives. The effects of first-person POV narratives were significantly stronger for stories that were written in the past-tense and that depicted the protagonist as being similar to message recipients.
Findings support a theoretical model of POV impact in which a first-person perspective increases identification with the character, thereby leading to higher levels of perceived susceptibility to the health threat. The practical implication is that the effectiveness of narrative persuasion is enhanced by using the first-person point of view, emphasizing target audience-protagonist similarities, and telling stories in the past tense.
Studies of coat color mutants have greatly contributed to the discovery of genes that regulate melanocyte development and function. Here, we generated Yy1 conditional knockout mice in the ...melanocyte-lineage and observed profound melanocyte deficiency and premature gray hair, similar to the loss of melanocytes in human piebaldism and Waardenburg syndrome. Although YY1 is a ubiquitous transcription factor, YY1 interacts with M-MITF, the Waardenburg Syndrome IIA gene and a master transcriptional regulator of melanocytes. YY1 cooperates with M-MITF in regulating the expression of piebaldism gene KIT and multiple additional pigmentation genes. Moreover, ChIP-seq identified genome-wide YY1 targets in the melanocyte lineage. These studies mechanistically link genes implicated in human conditions of melanocyte deficiency and reveal how a ubiquitous factor (YY1) gains lineage-specific functions by co-regulating gene expression with a lineage-restricted factor (M-MITF)-a general mechanism which may confer tissue-specific gene expression in multiple lineages.
Objective:
Little is known about parents’ willingness to vaccinate their children against COVID-19. We assessed the prevalence of vaccine hesitancy among parents with a child or adolescent aged 12-15 ...years, examined predictors of parents’ COVID-19 vaccine hesitancy, their reasons for resisting a pediatric COVID-19 vaccine, and the correlation between parents’ intentions to vaccinate their child and the acceptance of a vaccine for themselves.
Methods:
We conducted a national online survey of 637 parents of a child or adolescent aged 12-15 years in March 2021, before COVID-19 vaccines had been approved for this age group. We assessed univariate predictors of vaccine hesitancy, and we used logistic regression analysis to assess independent effects of variables on vaccine hesitancy.
Results:
Nearly one-third (28.9%; 95% CI, 25.5%-32.5%) of respondents reported pediatric vaccine hesitancy. Vaccine-hesitant parents were less knowledgeable about vaccines, more accepting of vaccine conspiracies, and less worried about COVID-19 risks to their child’s health than vaccine-accepting parents were. Vaccine hesitancy was higher among female (vs male), single (vs married/living as married), older (vs younger), low income (vs high income), non–college graduates (vs college graduates), and Republican (vs Democrat) parents. The primary concerns expressed by vaccine-hesitant parents pertained to vaccine safety rather than vaccine effectiveness. One-quarter of vaccine-hesitant parents preferred that their child obtain immunity through infection rather than vaccination. Non–vaccine-hesitant parents’ reasons for vaccinating focused on protecting the health of their child and others. Childhood COVID-19 vaccine acceptance was strongly associated with parents’ intentions to get the vaccine for themselves.
Conclusion:
A messaging strategy for effective public health interventions that includes educating the public about vaccination, countering misinformation about vaccine development and safety, and stressing the safety of approved COVID-19 vaccines may boost vaccine acceptance among vaccine-hesitant parents.
Pericytes are uniquely positioned within the neurovascular unit to serve as vital integrators, coordinators and effectors of many neurovascular functions, including angiogenesis, blood-brain barrier ...(BBB) formation and maintenance, vascular stability and angioarchitecture, regulation of capillary blood flow and clearance of toxic cellular byproducts necessary for proper CNS homeostasis and neuronal function. New studies have revealed that pericyte deficiency in the CNS leads to BBB breakdown and brain hypoperfusion resulting in secondary neurodegenerative changes. Here we review recent progress in understanding the biology of CNS pericytes and their role in health and disease.
PDF
