Author
Stefano Berto
Other affiliations: Leipzig University, Medical University of South Carolina, University of Texas at Dallas ...read more
Bio: Stefano Berto is an academic researcher from University of Texas Southwestern Medical Center. The author has contributed to research in topics: Medicine & DNA methylation. The author has an hindex of 14, co-authored 39 publications receiving 726 citations. Previous affiliations of Stefano Berto include Leipzig University & Medical University of South Carolina.
Papers
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TL;DR: It is shown that conditional embryonic deletion of Mef2c in cortical and hippocampal excitatory neurons (Emx1-lineage) produces a dramatic reduction in cortical network activity in vivo, and that MEF2C regulates E/I synapse density predominantly as a cell-autonomous, transcriptional repressor.
Abstract: Abnormal development of the brain contributes to intellectual disability, as well as to a number of psychiatric disorders, including schizophrenia and autism. As the brain develops, neurons establish connections with one another called synapses, which are either excitatory or inhibitory. At excitatory synapses, an electrical signal in the first cell increases the likelihood that the second cell will also produce an electrical signal. At inhibitory synapses, electrical activity in the first cell reduces the chances of the second cell producing an electrical signal. An imbalance between excitatory and inhibitory activity is one of the factors thought to give rise to neurodevelopmental disorders. Many individuals with schizophrenia, autism or intellectual disability possess mutations in, or near, a gene called MEF2C. This gene, which is active in both excitatory and inhibitory neurons, encodes a protein that regulates the activity of many other genes during brain development. Harrington, Raissi et al. therefore hypothesized that alterations in MEF2C might predispose individuals to neurodevelopmental disorders by disrupting the balance of excitatory and inhibitory synapses in the developing brain. To test this idea, Harrington, Raissi et al. generated mice that lack the Mef2c gene in a large proportion of their neurons throughout development. As predicted, the animals showed an imbalance of excitatory and inhibitory synapses in the brain’s outer layer, the cortex. They also displayed changes in behavior like those seen in autism. These included a loss of interest in social interaction and a reduction in vocalizations, suggesting impaired communication. Other behavioral changes included hyperactivity, repetitive movements and severe learning impairments: all features commonly observed in human neurodevelopmental disorders. The next challenge is to understand when, where and how MEF2C acts in the cortex to shape the balance of excitatory and inhibitory connections. Once this is known, further studies can test whether disrupting these processes leads directly to behaviors characteristic of autism, schizophrenia and intellectual disability. This may lead to the development of new drugs that can reverse or improve the symptoms of these conditions in affected individuals.
144 citations
TL;DR: It is shown that SCF from LepR+ cells is also necessary to maintain many c-kit+-restricted hematopoietic progenitors, while SCf from endothelial cells is required mainly by HSCs.
111 citations
TL;DR: This work identifies significant correlations between gene expression in the brain and functional activity by comparing fractional amplitude of low-frequency fluctuations (fALFF) from two independent human fMRI resting-state datasets to regional cortical gene expression from a newly generated RNA-seq dataset and two additional gene expression datasets to obtain robust and reproducible correlations.
103 citations
TL;DR: It is demonstrated that FoxP1 regulates the excitability of striatal medium spiny neurons and that reduction of Foxp1 correlates with defects in ultrasonic vocalizations, which support an integral role for FoxP 1 in regulating signaling pathways vulnerable in autism and the specific regulation of striatic pathways important for vocal communication.
Abstract: Mutations in the transcription factor Forkhead box p1 (FOXP1) are causative for neurodevelopmental disorders such as autism. However, the function of FOXP1 within the brain remains largely uncharacterized. Here, we identify the gene expression program regulated by FoxP1 in both human neural cells and patient-relevant heterozygous Foxp1 mouse brains. We demonstrate a role for FoxP1 in the transcriptional regulation of autism-related pathways as well as genes involved in neuronal activity. We show that Foxp1 regulates the excitability of striatal medium spiny neurons and that reduction of Foxp1 correlates with defects in ultrasonic vocalizations. Finally, we demonstrate that FoxP1 has an evolutionarily conserved role in regulating pathways involved in striatal neuron identity through gene expression studies in human neural progenitors with altered FOXP1 levels. These data support an integral role for FoxP1 in regulating signaling pathways vulnerable in autism and the specific regulation of striatal pathways important for vocal communication.
84 citations
TL;DR: The results provide novel and comprehensive methylome and transcriptome data from distinct cell populations within patient-derived brain tissues and demonstrate that cell type epigenetic-differentiated sites are preferentially targeted by disease-associated epigenetic dysregulation.
Abstract: The importance of cell type-specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. We generate cell type-specific whole-genome methylomes (N = 95) and transcriptomes (N = 89) from neurons and oligodendrocytes obtained from brain tissue of patients with schizophrenia and matched controls. The methylomes of the two cell types are highly distinct, with the majority of differential DNA methylation occurring in non-coding regions. DNA methylation differences between cases and controls are subtle compared to cell type differences, yet robust against permuted data and validated in targeted deep-sequencing analyses. Differential DNA methylation between control and schizophrenia tends to occur in cell type differentially methylated sites, highlighting the significance of cell type-specific epigenetic dysregulation in a complex neuropsychiatric disorder. Our results provide novel and comprehensive methylome and transcriptome data from distinct cell populations within patient-derived brain tissues. This data clearly demonstrate that cell type epigenetic-differentiated sites are preferentially targeted by disease-associated epigenetic dysregulation. We further show reduced cell type epigenetic distinction in schizophrenia.
59 citations
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Journal Article•
TL;DR: It is suggested that the natural selection against large insertion/deletion is so weak that a large amount of variation is maintained in a population.
11,521 citations
01 Feb 2015
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.
4,409 citations
01 Jan 2010
TL;DR: In this paper, the authors describe a scenario where a group of people are attempting to find a solution to the problem of "finding the needle in a haystack" in the environment.
Abstract: 中枢神経系疾患の治療は正常細胞（ニューロン）の機能維持を目的とするが，脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い．一方，脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める．いずれの場合にも，細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である．現在のところ最も研究の進んでいる細胞死の型はアポトーシスである．そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する．
2,716 citations
01 Jan 2011
TL;DR: The sheer volume and scope of data posed by this flood of data pose a significant challenge to the development of efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.
2,187 citations
Journal Article•
TL;DR: It is hypothesized that beta oscillations and/or coupling in the beta-band are expressed more strongly if the maintenance of the status quo is intended or predicted, than if a change is expected.
Abstract: In this review, we consider the potential functional role of beta-band oscillations, which at present is not yet well understood. We discuss evidence from recent studies on top-down mechanisms involved in cognitive processing, on the motor system and on the pathophysiology of movement disorders that suggest a unifying hypothesis: beta-band activity seems related to the maintenance of the current sensorimotor or cognitive state. We hypothesize that beta oscillations and/or coupling in the beta-band are expressed more strongly if the maintenance of the status quo is intended or predicted, than if a change is expected. Moreover, we suggest that pathological enhancement of beta-band activity is likely to result in an abnormal persistence of the status quo and a deterioration of flexible behavioural and cognitive control.
1,837 citations