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MYC-associated Factor X, MAX, controls the clock transcriptional network [RNA-Seq]

ABSTRACT: Purpose: Quantitative RT-PCR and ChIP analyses identified MAX as a transcriptional repressor of circadian BMAL1 target genes. The goal of this study is to compare the transcriptional effect of a knockdown of either MAX and BMAL1 in a human cell line (MDA-MB-231) Methods: Polyadenylated mRNA profiles of human breast cancer MDA-MB-231 cells with knocked down MAX or BMAL1 were generated by deep sequencing, in triplicate, using Illumina HiSeq 2000 sequencer. Cells transfected with a non-targeting siRNA sequence were used as a control. RNA sequencing counts were used to determine differentially expressed genes with DeSeq2 package included in the Galaxy web platform (usergalaxy.org). Differentially expressed genes (DEGs) were defined adopting an adjust P < 0.001 as a statistical cut-off value. Results: Transcript assembly and quantification of RNA-sequencing reads identified 4863 and 4247 differentially expressed genes (DEGs) upon knockdown of BMAL1 or MAX, respectively. The comparison of the two set of genes revealed that 2391 of siBMAL1 DEGs (almost 50%) were also differentially expressed in MAX-silenced cells. Heat map and clustering analysis of this sub-set of genes revealed that more than 90% (2241 out of 2391) were coherently altered in both conditions (i.e. their expression was altered in the same direction). Consistent with our quantitative RT-PCR experiments, genes belonging to the circadian rhythm signalling were altered by both MAX and BMAL1 silencing. Conclusion: This study indicate that MAX is a part of the molecular clock transcriptional network.

ORGANISM(S): Homo sapiens

PROVIDER: GSE127212 | GEO | 2020/04/29

REPOSITORIES: GEO

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MYC-associated factor X, MAX, binds BMAL1 targeted genomic regions with high affinity [ChIP-Seq]

Project description:Purpose: quantitavive RT-PCR and ChIP analyses suggested that the MYC-Associated factor X, MAX, and the essential circadian regulator, BMAL1, might be recruited on the same E-box containing regulatory regions within the promoters of clock target genes. To explore this possibility, we performed ChIP-seq experiments in human cancer MDA-MB-231 cells. Methods: Chromatin samples from human cancer MDA-MB-231 cells were immunoprecipitated with specific antibodies against BMAL1 and MAX proteins. Immunoprecipitated DNA was sequenced using Illumina HiSeq 2000 sequencer. Results: ChIP-seq analysis revealed a large number of genomic regions bound by MAX (around 13000 peaks), while BMAL1 binding was limited to about 800 regions. BMAl1 and MAX bound regions comprised both promoters and distal sites. Coherently with the circadian role of BMAL1 and its preference for E-box-containing sites, ontological annotation of BMAL1 bound regions showed a significant enrichment for circadian regulated genes and E-box motifs. The 85% of the BMAL bound sites overlapped with MAX bound regions. MAX enrichment was higher on the genomic regions co-bound by BMAL1 compared with MAX binding loci sites in which BMAL1 was not present, thus indicating that MAX/BMAL1 sites are bound by MAX with high affinity. Strikingly, MAX enrichment was observed on all E-box-containing promoters of the clock core genes.

2020-04-29 | GSE127192 | GEO

Transcriptome analysis of the circadian clock gene BMAL1 deletion with opposite carcinogenic effects

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Basic helix-loop-helix transcription factors MYC-MAX and CLOCK-BMAL1 associate with histones for E-box access

Project description:Basic helix-loop-helix (bHLH) transcription factors (TF) recognize E-boxes (CANNTG) and include over 100 members. Here we investigated how chromatinised E-boxes are engaged by two structurally diverse bHLH family members; the proto-oncogene MYC-MAX and the circadian TF, CLOCK-BMAL1. Both bind E-boxes preferentially near the nucleosomal entry/exit sites. Structural studies with artificial or endogenous nucleosome sequences illustrate that MYC-MAX/CLOCK-BMAL1 trigger DNA release from histones to gain access. The CLOCK-BMAL1 PAS dimerization domains engage the histone-octamer disc atop the H2A/H2B acidic patch, an interaction critical for circadian cycling. Binding of tandem E-boxes at endogenous DNA sequences is similarly achieved through direct interactions between two CLOCK-BMAL1 protomers and histones. At internal E-boxes, the MYC-MAX leucine zipper can also interact with histones H2B/H3, and its binding is indirectly enhanced by OCT4 elsewhere on the nucleosome. The nucleosomal E-box position and the type of bHLH dimerisation domain jointly determine the histone contact, the affinity, and the degree of competition/cooperativity with other nucleosome-bound factors.

2023-05-23 | GSE224589 | GEO

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