FoxO1 and FoxA1/2 form a complex on DNA and cooperate to open chromatin at insulin-regulated genes

2019 ◽  
Vol 97 (2) ◽  
pp. 118-129 ◽  
Author(s):  
Daniel Schill ◽  
Joshua Nord ◽  
Lisa Ann Cirillo
Keyword(s):  
Rna Polymerase Ii ◽  
Chromatin Remodeling ◽  
Insulin Treatment ◽  
Gene Activation ◽  
Open Chromatin ◽  
Active Chromatin ◽  
Developmental Context ◽  
Initial Activation ◽  
Pioneer Factors ◽  
Underlying Mechanisms

We have previously shown that cooperative, interdependent binding by the pioneer factors FoxO1 and FoxA1/2 is required for recruitment of RNA polymerase II and H3K27 acetylation to the promoters of insulin-regulated genes. However, the underlying mechanisms are unknown. In this study, we demonstrate that, in HepG2 cells, FoxO1 and FoxA2 form a complex on DNA that is disrupted by insulin treatment. Insulin-mediated phosphorylation of FoxO1 and FoxA2 does not impair their cooperative binding to mononucleosome particles assembled from the IGFBP1 promoter, indicating that direct disruption of complex formation by phosphorylation is not responsible for the loss of interdependent FoxO1:FoxA1/2 binding following insulin treatment. Since FoxO1 and FoxA1/2 binding is required for the establishment and maintenance of transcriptionally active chromatin at insulin-regulated genes, we hypothesized that cooperative FoxO1 and FoxA1/2 binding dictates the chromatin remodeling events required for the initial activation of these genes. In support of this idea, we demonstrate that FoxO1 and FoxA2 cooperatively open linker histone compacted chromatin templates containing the IGFBP1 promoter. Taken together, these results provide a mechanism for how interdependent FoxO1:FoxA1/2 binding is negatively impacted by insulin and provide a developmental context for cooperative gene activation by these factors.

scholarly journals SIRT6 promotes transcription of a subset of NRF2 targets by mono-ADP-ribosylating BAF170

2019 ◽  
Vol 47 (15) ◽  
pp. 7914-7928 ◽  
Author(s):  
Sarallah Rezazadeh ◽  
David Yang ◽  
Gregory Tombline ◽  
Matthew Simon ◽  
Sean P Regan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Rna Polymerase Ii ◽  
Chromatin Remodeling ◽  
Transcriptional Activation ◽  
Heme Oxygenase 1 ◽  
Nuclear Factor ◽  
Active Chromatin ◽  
Adp Ribosylation ◽  
Chromatin Remodeling Complex ◽  
A Subunit

Abstract SIRT6 is critical for activating transcription of Nuclear factor (erythroid-derived 2)-like 2 (NRF2) responsive genes during oxidative stress. However, while the mechanism of SIRT6-mediated silencing is well understood, the mechanism of SIRT6-mediated transcriptional activation is unknown. Here, we employed SIRT6 separation of function mutants to reveal that SIRT6 mono-ADP-ribosylation activity is required for transcriptional activation. We demonstrate that SIRT6 mono-ADP-ribosylation of BAF170, a subunit of BAF chromatin remodeling complex, is critical for activation of a subset of NRF2 responsive genes upon oxidative stress. We show that SIRT6 recruits BAF170 to enhancer region of the Heme oxygenase-1 locus and promotes recruitment of RNA polymerase II. Furthermore, SIRT6 mediates the formation of the active chromatin 10-kb loop at the HO-1 locus, which is absent in SIRT6 deficient tissue. These results provide a novel mechanism for SIRT6-mediated transcriptional activation, where SIRT6 mono-ADP-ribosylates and recruits chromatin remodeling proteins to mediate the formation of active chromatin loop.

scholarly journals Components of the Human SWI/SNF Complex Are Enriched in Active Chromatin and Are Associated with the Nuclear Matrix

1997 ◽  
Vol 137 (2) ◽  
pp. 263-274 ◽  
Author(s):  
Jose C. Reyes ◽  
Christian Muchardt ◽  
Moshe Yaniv
Keyword(s):  
Rna Polymerase Ii ◽  
Nuclear Matrix ◽  
Gene Activation ◽  
Nuclear Speckles ◽  
Active Chromatin ◽  
Subnuclear Localization ◽  
Potential Association ◽  
Immunofluorescence Studies ◽  
Chromatin Fractionation ◽  
Labeling Pattern

Biochemical and genetic evidence suggest that the SWI/SNF complex is involved in the remodeling of chromatin during gene activation. We have used antibodies specific against three human subunits of this complex to study its subnuclear localization, as well as its potential association with active chromatin and the nuclear skeleton. Immunofluorescence studies revealed a punctate nuclear labeling pattern that was excluded from the nucleoli and from regions of condensed chromatin. Dual labeling failed to reveal significant colocalization of BRG1 or hBRM proteins with RNA polymerase II or with nuclear speckles involved in splicing. Chromatin fractionation experiments showed that both soluble and insoluble active chromatin are enriched in the hSWI/SNF proteins as compared with bulk chromatin. hSWI/SNF proteins were also found to be associated with the nuclear matrix or nuclear scaffold, suggesting that a fraction of the hSWI/SNF complex could be involved in the chromatin organization properties associated with matrix attachment regions.

scholarly journals GFI1 tethers the NuRD complex to open and transcriptionally active chromatin in myeloid progenitors

2021 ◽  
Author(s):  
Anne Helness ◽  
Jennifer Fraszczak ◽  
Charles Joly-Beauparlant ◽  
Halil Bagci ◽  
Christian Trahan ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Target Genes ◽  
Myeloid Differentiation ◽  
Open Chromatin ◽  
Nurd Complex ◽  
Active Chromatin ◽  
Nucleosome Remodeling ◽  
Nucleosome Organization ◽  
Active Transcription ◽  
Neutrophil Differentiation

Abstract GFI1 is a SNAG-domain, DNA binding transcriptional repressor which controls myeloid differentiation, in particular the formation of neutrophils. Here we show that GFI1 interacts with the chromodomain helicase CHD4 and other components of the “Nucleosome remodeling and deacetylase” (NuRD) complex. In granulo-monocytic precursors, GFI1, CHD4 or GFI1/CHD4 complexes occupy sites of open chromatin enriched for histone marks associated with active transcription suggesting that GFI1 recruits the NuRD complex to target genes that are regulated by active or bivalent promoters and active enhancers. Our data also show that GFI1 and GFI1/CHD4 complexes occupy promoters of different sets of genes that are either enriched for IRF1 or SPI-1 consensus sites, respectively. During neutrophil differentiation, overall chromatin closure and depletion of H3K4me2 occurs at different degrees depending on whether GFI1, CHD4 or both are present, indicating that GFI1 affects the chromatin remodeling activity of the NuRD complex. Moreover, GFI1/CHD4 complexes regulate chromatin openness and histone modifications differentially to enable regulation of target genes affecting the signaling pathways of the immune response or nucleosome organization or cellular metabolic processes.

scholarly journals Sequential Histone Modifications at Hoxd4 Regulatory Regions Distinguish Anterior from Posterior Embryonic Compartments

2004 ◽  
Vol 24 (18) ◽  
pp. 8090-8103 ◽  
Author(s):  
Mojgan Rastegar ◽  
Laila Kobrossy ◽  
Erzsebet Nagy Kovacs ◽  
Isabel Rambaldi ◽  
Mark Featherstone
Keyword(s):  
Rna Polymerase Ii ◽  
Histone Modifications ◽  
Chromatin Immunoprecipitation ◽  
Gene Activation ◽  
Open Chromatin ◽  
Rna Pol Ii ◽  
Regulatory Regions ◽  
Pol Ii ◽  
Embryonic Tissues ◽  
Intervening Sequences

ABSTRACT Hox genes are differentially expressed along the embryonic anteroposterior axis. We used chromatin immunoprecipitation to detect chromatin changes at the Hoxd4 locus during neurogenesis in P19 cells and embryonic day 8.0 (E8.0) and E10.5 mouse embryos. During Hoxd4 induction in both systems, we observed that histone modifications typical of transcriptionally active chromatin occurred first at the 3′ neural enhancer and then at the promoter. Moreover, the sequential distribution of histone modifications between E8.0 and E10.5 was consistent with a spreading of open chromatin, starting with the enhancer, followed by successively more 5′ intervening sequences, and culminating at the promoter. Neither RNA polymerase II (Pol II) nor CBP associated with the inactive gene. During Hoxd4 induction, CBP and RNA Pol II were recruited first to the enhancer and then to the promoter. Whereas the CBP association was transient, RNA Pol II remained associated with both regulatory regions. Histone modification and transcription factor recruitment occurred in posterior, Hox-expressing embryonic tissues, but never in anterior tissues, where such genes are inactive. Together, our observations demonstrate that the direction of histone modifications at Hoxd4 mirrors colinear gene activation across Hox clusters and that the establishment of anterior and posterior compartments is accompanied by the imposition of distinct chromatin states.

scholarly journals KrasG12D induces changes in chromatin territories that differentially impact early nuclear reprogramming in pancreatic cells

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Angela J. Mathison ◽  
Romica Kerketta ◽  
Thiago Milech de Assuncao ◽  
Elise Leverence ◽  
Atefeh Zeighami ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Gene Activation ◽  
Time Dependent ◽  
Ductal Adenocarcinoma ◽  
Specific Gene ◽  
Open Chromatin ◽  
Gene Promoters ◽  
Transcriptional Program ◽  
Kras Mutations ◽  
Pancreatic Cells

Abstract Background Pancreatic ductal adenocarcinoma initiation is most frequently caused by Kras mutations. Results Here, we apply biological, biochemical, and network biology methods to validate GEMM-derived cell models using inducible KrasG12D expression. We describe the time-dependent, chromatin remodeling program that impacts function during early oncogenic signaling. We find that the KrasG12D-induced transcriptional response is dominated by downregulated expression concordant with layers of epigenetic events. More open chromatin characterizes the ATAC-seq profile associated with a smaller group of upregulated genes and epigenetic marks. RRBS demonstrates that promoter hypermethylation does not account for the silencing of the extensive gene promoter network. Moreover, ChIP-Seq reveals that heterochromatin reorganization plays little role in this early transcriptional program. Notably, both gene activation and silencing primarily depend on the marking of genes with a combination of H3K27ac, H3K4me3, and H3K36me3. Indeed, integrated modeling of all these datasets shows that KrasG12D regulates its transcriptional program primarily through unique super-enhancers and enhancers, and marking specific gene promoters and bodies. We also report chromatin remodeling across genomic areas that, although not contributing directly to cis-gene transcription, are likely important for KrasG12D functions. Conclusions In summary, we report a comprehensive, time-dependent, and coordinated early epigenomic program for KrasG12D in pancreatic cells, which is mechanistically relevant to understanding chromatin remodeling events underlying transcriptional outcomes needed for the function of this oncogene.

scholarly journals GFI1 tethers the NuRD complex to open and transcriptionally active chromatin in myeloid progenitors

2021 ◽  
Author(s):  
Tarik Moroy ◽  
Anne Helness ◽  
Jennifer Fraszczak ◽  
Charles Joly-Beauparlant ◽  
Halil Bagci ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Target Genes ◽  
Myeloid Differentiation ◽  
Open Chromatin ◽  
Nurd Complex ◽  
Active Chromatin ◽  
Nucleosome Remodeling ◽  
Nucleosome Organization ◽  
Active Transcription ◽  
Neutrophil Differentiation

GFI1 is a SNAG-domain, DNA binding transcriptional repressor which controls myeloid differentiation, in particular the formation of neutrophils. Here we show that GFI1 interacts with the chromodomain helicase CHD4 and other components of the "Nucleosome remodeling and deacetylase" (NuRD) complex. In granulo-monocytic precursors, GFI1, CHD4 or GFI1/CHD4 complexes occupy sites of open chromatin enriched for histone marks associated with active transcription suggesting that GFI1 recruits the NuRD complex to target genes that are regulated by active or bivalent promoters and active enhancers. Our data also show that GFI1 and GFI1/CHD4 complexes occupy promoters of different sets of genes that are either enriched for IRF1 or SPI-1 consensus sites, respectively. During neutrophil differentiation, overall chromatin closure and depletion of H3K4me2 occurs at different degrees depending on whether GFI1, CHD4 or both are present, indicating that GFI1 affects the chromatin remodeling activity of the NuRD complex. Moreover, GFI1/CHD4 complexes regulate chromatin openness and histone modifications differentially to enable regulation of target genes affecting the signaling pathways of the immune response or nucleosome organization or cellular metabolic processes.

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