Brd4-bound enhancers drive cell-intrinsic sex differences in glioblastoma

Abstract

Consistent sex differences in incidence and outcome have been reported in numerous cancers including brain tumors. GBM, the most common and aggressive primary brain tumor, occurs with higher incidence and shorter survival in males compared to females. Brd4 is essential for regulating transcriptome-wide gene expression and specifying cell identity, including that of GBM. We report that sex-biased Brd4 activity drives sex differences in GBM and renders male and female tumor cells differentially sensitive to BET inhibitors. The observed sex differences in BETi treatment strongly indicate that sex differences in disease biology translate into sex differences in therapeutic responses. This has critical implications for clinical use of BET inhibitors further affirming the importance of inclusion of sex as a biological variable.

SciScore for 10.1101/199059: (What is this?)

Please note, not all rigor criteria are appropriate for all manuscripts.

Table 1: Rigor

NIH rigor criteria are not applicable to paper type.

Table 2: Resources

Software and Algorithms
Sentences	Resources
Reads were mapped to the mm10 reference genome using Novoalign (version 3.08.02; Novocraft	Novoalign suggested: (NovoAlign, RRID:SCR_014818)
ChlP-seq data sets for H3K27ac were aligned to the murine genome build mm10 using Bowtie2 (version 2.3.4.3) and only uniquely aligning reads were used for downstream analyses (71).	Bowtie2 suggested: (Bowtie 2, RRID:SCR_016368)
The resulting peak files were used as inputs for DiffBind (version 3.5) to derive consensus peak sets (74, 75).	DiffBind suggested: (DiffBind, RRID:SCR_012918)
The differential enrichment of H3K27Ac signals between male and female analysis was …

SciScore for 10.1101/199059: (What is this?)

Please note, not all rigor criteria are appropriate for all manuscripts.

Table 1: Rigor

NIH rigor criteria are not applicable to paper type.

Table 2: Resources

Software and Algorithms
Sentences	Resources
Reads were mapped to the mm10 reference genome using Novoalign (version 3.08.02; Novocraft	Novoalign suggested: (NovoAlign, RRID:SCR_014818)
ChlP-seq data sets for H3K27ac were aligned to the murine genome build mm10 using Bowtie2 (version 2.3.4.3) and only uniquely aligning reads were used for downstream analyses (71).	Bowtie2 suggested: (Bowtie 2, RRID:SCR_016368)
The resulting peak files were used as inputs for DiffBind (version 3.5) to derive consensus peak sets (74, 75).	DiffBind suggested: (DiffBind, RRID:SCR_012918)
The differential enrichment of H3K27Ac signals between male and female analysis was carried out with Diffbind using DESeq2 (method = DBA_DESEQ2) with libraries normalized to total library size.	DESeq2 suggested: (DESeq, RRID:SCR_000154)
RNA-seq data sets were aligned to the transcriptome and the whole-genome with STAR (version 2.7.0) (76)	STAR suggested: (STAR, RRID:SCR_015899)
GTF) file were derived from uniquely aligned reads using HTSeq (version 0.11.1) (77).	HTSeq suggested: (HTSeq, RRID:SCR_005514)
The server ftp links are below: Calling Card data and processed files: https://htcf.wustl.edu/files/pX76jgeW ChlP-seq data and processed files: https://htcf.wustl.edu/files/LdbbjVd3 RNA-seq data and processed files: https://htcf.wustl.edu/files/NeAbNQX2 Additionally, these files have been deposited in the Short Read Archive/GEO database (	Short Read Archive/GEO suggested: None
(http://www.ncbi.nlm.nih.gov/geo/).	http://www.ncbi.nlm.nih.gov/geo/ suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)

Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

Results from TrialIdentifier: No clinical trial numbers were referenced.

Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

Results from JetFighter: We did not find any issues relating to colormaps.

Results from rtransparent:

Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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No protocol registration statement was detected.

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Brd4-bound enhancers drive cell-intrinsic sex differences in glioblastoma

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