81 research outputs found
Discovering Neuronal Cell Types and Their Gene Expression Profiles Using a Spatial Point Process Mixture Model
Cataloging the neuronal cell types that comprise circuitry of individual
brain regions is a major goal of modern neuroscience and the BRAIN initiative.
Single-cell RNA sequencing can now be used to measure the gene expression
profiles of individual neurons and to categorize neurons based on their gene
expression profiles. While the single-cell techniques are extremely powerful
and hold great promise, they are currently still labor intensive, have a high
cost per cell, and, most importantly, do not provide information on spatial
distribution of cell types in specific regions of the brain. We propose a
complementary approach that uses computational methods to infer the cell types
and their gene expression profiles through analysis of brain-wide single-cell
resolution in situ hybridization (ISH) imagery contained in the Allen Brain
Atlas (ABA). We measure the spatial distribution of neurons labeled in the ISH
image for each gene and model it as a spatial point process mixture, whose
mixture weights are given by the cell types which express that gene. By fitting
a point process mixture model jointly to the ISH images, we infer both the
spatial point process distribution for each cell type and their gene expression
profile. We validate our predictions of cell type-specific gene expression
profiles using single cell RNA sequencing data, recently published for the
mouse somatosensory cortex. Jointly with the gene expression profiles, cell
features such as cell size, orientation, intensity and local density level are
inferred per cell type
Genome-Wide Profiling of H3K56 Acetylation and Transcription Factor Binding Sites in Human Adipocytes
The growing epidemic of obesity and metabolic diseases calls for a better understanding of adipocyte biology. The regulation of transcription in adipocytes is particularly important, as it is a target for several therapeutic approaches. Transcriptional outcomes are influenced by both histone modifications and transcription factor binding. Although the epigenetic states and binding sites of several important transcription factors have been profiled in the mouse 3T3-L1 cell line, such data are lacking in human adipocytes. In this study, we identified H3K56 acetylation sites in human adipocytes derived from mesenchymal stem cells. H3K56 is acetylated by CBP and p300, and deacetylated by SIRT1, all are proteins with important roles in diabetes and insulin signaling. We found that while almost half of the genome shows signs of H3K56 acetylation, the highest level of H3K56 acetylation is associated with transcription factors and proteins in the adipokine signaling and Type II Diabetes pathways. In order to discover the transcription factors that recruit acetyltransferases and deacetylases to sites of H3K56 acetylation, we analyzed DNA sequences near H3K56 acetylated regions and found that the E2F recognition sequence was enriched. Using chromatin immunoprecipitation followed by high-throughput sequencing, we confirmed that genes bound by E2F4, as well as those by HSF-1 and C/EBPα, have higher than expected levels of H3K56 acetylation, and that the transcription factor binding sites and acetylation sites are often adjacent but rarely overlap. We also discovered a significant difference between bound targets of C/EBPα in 3T3-L1 and human adipocytes, highlighting the need to construct species-specific epigenetic and transcription factor binding site maps. This is the first genome-wide profile of H3K56 acetylation, E2F4, C/EBPα and HSF-1 binding in human adipocytes, and will serve as an important resource for better understanding adipocyte transcriptional regulation.Singapore. Agency for Science, Technology and Research (National Science Scholarship )Massachusetts Institute of Technology (Eugene Bell Career Development Chair)National Science Foundation (U.S.) (Award No. DBI-0821391)Pfizer Inc
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Discovering Neuronal Cell Types and Their Gene Expression Profiles Using a Spatial Point Process Mixture Model
Cataloging the neuronal cell types that comprise circuitry of individual
brain regions is a major goal of modern neuroscience and the BRAIN initiative.
Single-cell RNA sequencing can now be used to measure the gene expression
profiles of individual neurons and to categorize neurons based on their gene
expression profiles. While the single-cell techniques are extremely powerful
and hold great promise, they are currently still labor intensive, have a high
cost per cell, and, most importantly, do not provide information on spatial
distribution of cell types in specific regions of the brain. We propose a
complementary approach that uses computational methods to infer the cell types
and their gene expression profiles through analysis of brain-wide single-cell
resolution in situ hybridization (ISH) imagery contained in the Allen Brain
Atlas (ABA). We measure the spatial distribution of neurons labeled in the ISH
image for each gene and model it as a spatial point process mixture, whose
mixture weights are given by the cell types which express that gene. By fitting
a point process mixture model jointly to the ISH images, we infer both the
spatial point process distribution for each cell type and their gene expression
profile. We validate our predictions of cell type-specific gene expression
profiles using single cell RNA sequencing data, recently published for the
mouse somatosensory cortex. Jointly with the gene expression profiles, cell
features such as cell size, orientation, intensity and local density level are
inferred per cell type
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