Cistrome-partitioning reveals convergence of somatic mutations and risk-variants on master transcription regulators in primary prostate tumors
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PROVIDER: PRJNA565782 | ENA |
REPOSITORIES: ENA
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Project description:Thousands of noncoding somatic Single Nucleotide Variants (SNVs) of unknown function are reported in tumors. Partitioning the genome according to cistromes, reveals the enrichment of somatic SNVs in prostate tumors as opposed to adjacent normal tissue cistromes of master transcription regulators, including AR, FOXA1 and HOXB13. This parallels enrichment of prostate cancer genetic predispositions over these transcription regulators’ tumor cistromes, exemplified at the 8q24 locus harboring both risk-variants and somatic SNVs in cis-regulatory elements, upregulating MYC expression and altering the binding of transcription regulators to DNA. However, Massively-Parallel Reporter Assays reveal that few SNVs can alter the transactivation potential of individual CREs. Instead, SNVs accumulate, similarly to inherited riskvariants, in cistromes of master transcription regulators required for prostate cancer development. Significance Difficulties in inferring the biological significance of noncoding mutations have limited their inclusion in precision genomics medicine pipelines. Most attempts to delineate a role for noncoding mutations relied on detecting evidence for positive selection within individual CREs, such as reported for the TERT gene promoter. By considering the enrichment of noncoding mutations in cistromes as opposed to individual CREs, we reveal their specificity towards master transcription regulators that promote prostate cancer development, a feature shared with inherited risk-variants. Overall, our work provides a blueprint for the functional interpretation of noncoding mutations in genomic tests relying on defining cis-regulatory units according to cistrome-partitioning to identify cancer driver transcription regulators.
2019-12-01 | GSE137527 | GEO
Project description:Thousands of noncoding somatic Single Nucleotide Variants (SNVs) of unknown
function are reported in tumors. Partitioning the genome according to cistromes,
reveals the enrichment of somatic SNVs in prostate tumors as opposed to adjacent
normal tissue cistromes of master transcription regulators, including AR, FOXA1 and
HOXB13. This parallels enrichment of prostate cancer genetic predispositions over
these transcription regulators’ tumor cistromes, exemplified at the 8q24 locus harboring
both risk-variants and somatic SNVs in cis-regulatory elements, upregulating MYC
expression and altering the binding of transcription regulators to DNA. However, Massively-Parallel Reporter Assays reveal that few SNVs can alter the transactivation
potential of individual CREs. Instead, SNVs accumulate, similarly to inherited riskvariants,
in cistromes of master transcription regulators required for prostate cancer
development.
Difficulties in inferring the biological significance of noncoding mutations have limited
their inclusion in precision genomics medicine pipelines. Most attempts to delineate a
role for noncoding mutations relied on detecting evidence for positive selection within
individual CREs, such as reported for the TERT gene promoter. By considering the
enrichment of noncoding mutations in cistromes as opposed to individual CREs, we
reveal their specificity towards master transcription regulators that promote prostate
cancer development, a feature shared with inherited risk-variants. Overall, our work
provides a blueprint for the functional interpretation of noncoding mutations in genomic
tests relying on defining cis-regulatory units according to cistrome-partitioning to
identify cancer driver transcription regulators.
| EGAS00001003928 | EGA
Project description:Master transcription factors are the gatekeepers of lineage identity. As such, they have been a major focus of efforts to manipulate cell fate for therapeutic purposes. The ETS transcription factor PU.1 has a potent ability to confer macrophage phenotypes on cells already committed to a different lineage, but how it overcomes the presence of other master regulators is not known. The nuclear receptor PPARγ is the master regulator of the adipose lineage, and its genomic binding pattern is well characterized in adipocytes. Here, we show that when expressed at macrophage levels in mature adipocytes, PU.1 bound a large fraction of its macrophage sites, where it induced chromatin opening and the expression of macrophage target genes. Strikingly, PU.1 markedly reduced the genomic binding of PPARγ without changing its abundance. PU.1 expression repressed genes with nearby adipocyte-specific PPARγ binding sites, while a common macrophage-adipocyte gene expression program was retained. Together, these data reveal unexpected lability within the adipocyte PPARγ cistrome and show that even in terminally differentiated cells, PU.1 can remodel the cistrome of another master regulator. Microarray expression profiling was performed on 3T3-L1 adipocytes from two treatment groups: (1) adipocytes transduced with a control adenovirus expressing beta-galactosidase (LACZ-Ads) and (2) adipocytes transduced with an adenovirus expressing full-length murine PU.1 cDNA (PU.1-Ads). Each sample group consists of four biological replicates which are here defined as separate differentiations of mature 3T3-L1 adipocytes and adenoviral infections. Each replicate was hybridized to an individual array for a total of eight arrays.
2013-06-27 | E-GEOD-48344 | biostudies-arrayexpress
Project description:Master transcription factors are the gatekeepers of lineage identity. As such, they have been a major focus of efforts to manipulate cell fate for therapeutic purposes. The ETS transcription factor PU.1 has a potent ability to confer macrophage phenotypes on cells already committed to a different lineage, but how it overcomes the presence of other master regulators is not known. The nuclear receptor PPARγ is the master regulator of the adipose lineage, and its genomic binding pattern is well characterized in adipocytes. Here, we show that when expressed at macrophage levels in mature adipocytes, PU.1 bound a large fraction of its macrophage sites, where it induced chromatin opening and the expression of macrophage target genes. Strikingly, PU.1 markedly reduced the genomic binding of PPARγ without changing its abundance. PU.1 expression repressed genes with nearby adipocyte-specific PPARγ binding sites, while a common macrophage-adipocyte gene expression program was retained. Together, these data reveal unexpected lability within the adipocyte PPARγ cistrome and show that even in terminally differentiated cells, PU.1 can remodel the cistrome of another master regulator.
2013-06-27 | GSE48344 | GEO
Project description:"Master" transcription factors are the gatekeepers of lineage identity. As such, they have been a major focus of efforts to manipulate cell fate for therapeutic purposes. The ETS transcription factor PU.1 has a potent ability to confer macrophage phenotypes on cells already committed to a different lineage, but how it overcomes the presence of other master regulators is not known. The nuclear receptor PPARM-NM-3 is the master regulator of the adipose lineage, and its genomic binding pattern is well characterized in adipocytes. Here, we show that when expressed at macrophage levels in mature adipocytes, PU.1 bound a large fraction of its macrophage sites, where it induced chromatin opening and the expression of macrophage target genes. Strikingly, PU.1 markedly reduced the genomic binding of PPARM-NM-3 without changing its abundance. PU.1 expression repressed genes with nearby adipocyte-specific PPARM-NM-3 binding sites, while a common macrophage-adipocyte gene expression program was retained. Together, these data reveal unexpected lability within the adipocyte PPARM-NM-3 cistrome and show that even in terminally differentiated cells, PU.1 can remodel the cistrome of another master regulator. ChIP-seq was performed on 3T3-L1 adipocytes from two treatment groups: (1) adipocytes transduced with a control adenovirus expressing beta-galactosidase (LACZ-Ads) and (2) adipocytes transduced with an adenovirus expressing full-length murine PU.1 cDNA (PU.1-Ads). Nuclear lysates from each group were used for PPARg ChIP. For PU.1-Ads, PU.1 ChIP was also performed. To generate chromatin for ChIP-seq, DNA from three immunoprecipitations per condition was pooled. This process was repreated from a second set of L1 adipocytes to generate two biological replicates for sequencing. Genomic input DNA was sequenced from the first biological replicate only.
2013-06-27 | E-GEOD-48343 | biostudies-arrayexpress
Project description:"Master" transcription factors are the gatekeepers of lineage identity. As such, they have been a major focus of efforts to manipulate cell fate for therapeutic purposes. The ETS transcription factor PU.1 has a potent ability to confer macrophage phenotypes on cells already committed to a different lineage, but how it overcomes the presence of other master regulators is not known. The nuclear receptor PPARγ is the master regulator of the adipose lineage, and its genomic binding pattern is well characterized in adipocytes. Here, we show that when expressed at macrophage levels in mature adipocytes, PU.1 bound a large fraction of its macrophage sites, where it induced chromatin opening and the expression of macrophage target genes. Strikingly, PU.1 markedly reduced the genomic binding of PPARγ without changing its abundance. PU.1 expression repressed genes with nearby adipocyte-specific PPARγ binding sites, while a common macrophage-adipocyte gene expression program was retained. Together, these data reveal unexpected lability within the adipocyte PPARγ cistrome and show that even in terminally differentiated cells, PU.1 can remodel the cistrome of another master regulator.
2013-06-27 | GSE48343 | GEO
Project description:Components of the transcriptional machinery are dynamically compartmentalized by weak multivalent interactions, yet we know little about how specificity or selectivity of partitioning is achieved. Here we show that condensates composed of the intrinsically disordered region (IDR) of MED1 (MED1_IDR) selectively partition positive regulators of transcription(SPT6, CTR9, IWS1) with RNA Pol II while excluding negative regulators of transcription (NELF and HP1a).This selective compartmentalization by MED1_IDR is sufficient to activate transcription and is required for gene activation during a cell state transition. Surprisingly, the IDRs of partitioned proteins are sufficient to recapitulate selective compartmentalization. We find that IDR-mediated selective partitioning requires multivalent blocks of positive and negative charge on MED1_IDR and IDRs of partitioned proteins. The charge patterns required for partitioning are also required for gene activation. These findings demonstrate that proteins can be functionally compartmentalized by specific multivalent interactions driven by the charge patterning within disordered regions.
2023-01-03 | GSE210875 | GEO
Project description:Rewiring of master transcription factor cistrome during high-grade serous ovarian cancer development
| PRJNA946801 | ENA
Project description:Rewiring of master transcription factor cistrome during high-grade serous ovarian cancer development [Hi-C]
| PRJNA954375 | ENA
Project description:Rewiring of master transcription factor cistrome during high-grade serous ovarian cancer development [RNA-seq]
| PRJNA944554 | ENA