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AFF1-HEXIM1 cooperation suppresses rapid-response differentiation initiators to enforce epidermal progenitor maintenance

ABSTRACT: In this study we identified an essential role of the SEC, a crucial regulator of Pol II dynamics, in repressing differentiation for epidermal progenitor maintenance. This repression of differentiation is specifically mediated by the scaffold protein AFF1, but not AFF4. Mechanistically, we find that AFF1-SEC associates with the HEXIM1-containing inactive-PTEFb to directly repress a group of rapid-response genes, which feature robust Pol II pausing near their promoters in the progenitor state. De-repression of these genes occurs within 3 hours of SEC-PTEFb disruption by the peptidomimetic inhibitors. These rapid-response genes include the transcription factor ATF3. Increased ATF3 level is sufficient to promote the expression of key differentiation activators, such as PRDM1, OVOL1, GRHL3 and ZNF750. Furthermore, we find that the dissociation of inactivate P-TEFb from SEC mediates the earliest events of PKC signaling, in triggering epidermal differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182959 | GEO | 2022/06/24

REPOSITORIES: GEO

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AFF1-HEXIM1 cooperation suppresses rapid-response differentiation initiators to enforce epidermal progenitor maintenance

Project description:AFF1-HEXIM1 cooperation suppresses rapid-response differentiation initiators to enforce epidermal progenitor maintenance

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Distinct roles of the two SEC scaffold proteins, AFF1 and AFF4, in regulating RNA Pol II transcription elongation [RNA-seq]

Project description:The P-TEFb-containing super elongation complex (SEC) plays the essential role in transcriptional elongation control. The AF4/FMR2 family members AFF1 and AFF4 are the central scaffold proteins of SEC, associated with different human diseases. However, their specific roles in transcriptional control remain unclear. Here, we report that AFF1 and AFF4 show distinct genomic distribution patterns around TSS. AFF1 binds upstream of TSS, while AFF4 is enriched downstream of TSS. Pol II occupancies are reduced genome-widely after depletion of AFF1, but not AFF4. Interestingly, in a subset of active genes with broad AFF4 binding signature, AFF4 disruption causes slow elongation and early termination, while AFF1 deletion mirrors the transcriptional defects observed in the fast Pol II mutant. Furthermore, AFF4 knockdown leads to increased AFF1 levels at chromatin, and vice versa. In summary, our data demonstrate that AFF1 and AFF4 function, to some extent, antagonistically to ensure proper Pol II transcription.

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Distinct roles of the two SEC scaffold proteins, AFF1 and AFF4, in regulating RNA Pol II transcription elongation [ChIP-seq 2]

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Distinct roles of the two SEC scaffold proteins, AFF1 and AFF4, in regulating RNA Pol II transcription elongation [ChIP-seq 1]

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Distinct roles of the two SEC scaffold proteins, AFF1 and AFF4, in regulating RNA Pol II transcription elongation [ChiP-seq 3]

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Acute perturbation strategies in interrogating RNA Polymerase II elongation factor function in gene expression

Project description:The regulation of gene expression catalyzed by RNA Polymerase II (Pol II) requires a host of accessory factors to ensure cell growth, differentiation, and survival under environmental stress. Here, using the auxin-inducible degradation (AID) system to study transcriptional activities of the bromodomain and extra terminal domain (BET) and Super Elongation Complex (SEC) families, we found that the CDK9-containing BRD4 complex is required for the release of Pol II from promoter-proximal pausing for most genes, while the CDK9-containing SEC is required for activated transcription in the heat shock response. By using both the Proteolysis-targeting chimera (PROTAC) dBET6 and the AID system, we found that dBET6 treatment results in two major effects: the increased pausing due to BRD4 loss, and reduced enhancer activity attributable to BRD2 loss. In the heat shock response, while auxin-mediated depletion of the AFF4 subunit of SEC has a more severe defect than AFF1 depletion, simultaneous depletion of AFF1 and AFF4 leads to a stronger attenuation of the heat shock response, similar to treatment with the SEC inhibitor KL-1, suggesting a possible redundancy among SEC family members. This study highlights the usefulness of orthogonal acute depletion/inhibition strategies to identify distinct and redundant biological functions among Pol II elongation factor paralogs.

2021-01-15 | GSE145525 | GEO

The SEC family of RNA Polymerase II elongation factors: gene target specificity and transcriptional output

Project description:The elongation stage of transcription is a highly regulated in metazoan. We previously purified the AFF1/AFF4-containing Super Elongation Complex (SEC) as a major regulator of development and cancer pathogenesis. Here, we report the biochemical isolation of SEC-like 2 (SEC-L2) and SEC-like 3 (SEC-L3) containing AFF2 and AFF3 in association with P-TEFb, ENL, and AF9. The SEC family members demonstrate high levels of Pol II CTD kinase activity, however, only SEC is required for the proper induction of the HSP70 gene upon stress. Genome-wide mRNA-seq analyses demonstrate that SEC-L2-3 control the expression of different subsets of genes, while AFF4/SEC plays a more dominant role in rapid gene expression in cells. MYC is one of the direct targets of AFF4/SEC, and the SEC requirement to the MYC gene regulates its expression in different cancer cells bearing either acute myeloid or lymphoid leukemia. These findings suggest that AFF4/SEC could be a potential therapeutic target for the treatment of leukemia or other cancers associated with MYC overexpression. RNA-seq in human embyonic kidney 293T cells of wild-type and after RNAi of AFF2, AFF3, AFF4. ChIP-seq of AFF4 and Pol2 in human 293T cells.

2012-05-01 | E-GEOD-34097 | biostudies-arrayexpress

The SEC family of RNA Polymerase II elongation factors: gene target specificity and transcriptional output

2012-05-02 | GSE34097 | GEO

Gene target specificity of the Super Elongation Complex (SEC) family: How HIV-1 Tat employs selected SEC members to activate viral transcription

Project description:The AF4/FMR2 proteins AFF1 and AFF4 act as a scaffold to assemble the Super Elongation Complex (SEC) that strongly activates transcriptional elongation of HIV-1 and cellular genes. Although they can dimerize, it is unclear whether the dimers exist and function within a SEC in vivo. Furthermore, it is unknown whether AFF1 and AFF4 function similarly in mediating SEC-dependent activation of diverse genes. Providing answers to these questions, our current study shows that AFF1 and AFF4 reside in separate SECs that display largely distinct gene target specificities. While the AFF1-SEC is more potent in supporting HIV-1 transactivation by the viral Tat protein, the AFF4-SEC is more important for HSP70 induction upon heat shock. The functional difference between AFF1 and AFF4 in Tat-transactivation has been traced to a single amino acid variation between the two proteins, which causes them to enhance the affinity of Tat for P-TEFb, a key SEC component, with different efficiency. Finally, genome-wide analysis confirms that the genes regulated by AFF1- and AFF4-SEC are largely non-overlapping and perform distinct functions. Thus, the SEC represents a family of related complexes that exist to increase the regulatory diversity and gene control options during transactivation of diverse cellular and viral genes. RNA-seq in HeLa cells of wild-type and after RNAi of AFF1 or AFF4.

2015-05-20 | E-GEOD-69021 | biostudies-arrayexpress

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