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MeCP2 Interacts with the Super Elongation Complex to Regulate Transcription (RNA-Seq)

ABSTRACT: Loss-of-function mutations in methyl-CpG binding protein 2 (MECP2) cause the neurodevelopmental disorder, Rett syndrome (RTT). The molecular mechanisms underlying MeCP2 function remain poorly understood. Here, using a MECP2 gain-of-function Drosophila model, we screened for genetic modifiers of MECP2-induced toxicity. Our approach identified several subunits of the Drosophila super elongation complex (SEC), a P-TEFb containing elongation factor that releases promoter-proximally paused RNA polymerase II (RNA pol II), as genetic interactors of MECP2. MeCP2 directly interacts with AFF4, the scaffold of the SEC, and facilitates its binding on a subset of genes that regulate neuronal development and synaptic function in the mouse cortex. Furthermore, genes with reduced AFF4 binding showed reduced RNA pol II binding in their genebody and decreased RNA expression in Mecp2 null mice. Taken together, we propose that MeCP2 interacts with the SEC to facilitate the release of RNA pol II and thereby support gene expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE275332 | GEO | 2025/11/03

REPOSITORIES: GEO

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MeCP2 Interacts with the Super Elongation Complex to Regulate Transcription (ChIP-Seq)

Project description:Loss-of-function mutations in methyl-CpG binding protein 2 (MECP2) cause the neurodevelopmental disorder, Rett syndrome (RTT). The molecular mechanisms underlying MeCP2 function remain poorly understood. Here, using a MECP2 gain-of-function Drosophila model, we screened for genetic modifiers of MECP2-induced toxicity. Our approach identified several subunits of the Drosophila super elongation complex (SEC), a P-TEFb containing elongation factor that releases promoter-proximally paused RNA polymerase II (RNA pol II), as genetic interactors of MECP2. MeCP2 directly interacts with AFF4, the scaffold of the SEC, and facilitates its binding on a subset of genes that regulate neuronal development and synaptic function in the mouse cortex. Furthermore, genes with reduced AFF4 binding showed reduced RNA pol II binding in their genebody and decreased RNA expression in Mecp2 null mice. Taken together, we propose that MeCP2 interacts with the SEC to facilitate the release of RNA pol II and thereby support gene expression.

2025-11-03 | GSE275329 | GEO

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

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 3]

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

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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

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

Allosteric transcription stimulation by super elongation complex

Project description:The super elongation complex (SEC) contains the positive transcription elongation factor b (P-TEFb) and a subcomplex, ELL2-EAF1, which stimulates transcription elongation by RNA polymerase II (Pol II). Here we report the cryo-EM structure of ELL2-EAF1 bound to a Pol II elongation complex at 2.8 Å resolution. The ELL2-EAF1 dimerization module directly binds the Pol II lobe, explaining how SEC delivers P-TEFb to Pol II. The same site on the lobe also binds the initiation factor TFIIF, consistent with SEC binding only after the transition from transcription initiation to elongation. Structure-guided functional analysis shows that elongation stimulation requires the dimerization module and an ELL2 protein linker that tethers this module to the Pol II protrusion. Our results show that SEC stimulates elongation allosterically and indicate that this stimulation involves stabilization of a further closed conformation of the Pol II active center cleft.

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