Author response: Identification of the transcription factor ZEB1 as a central component of the adipogenic gene regulatory network

Gubelmann, Carine; Schwalie, Petra; Raghav, Sunil K.; Röder, Eva; Delessa, Tenagne; Kiehlmann, Elke; Waszak, Sebastian M.; Corsinotti, Andrea; Udin, Gilles; Holcombe, Wiebke; Rudofsky, Gottfried; Trono, Didier; Wolfrum, Christian; Deplancke, Bart

doi:10.7554/elife.03346.020

Cited by 2 publications

(2 citation statements)

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“…Multiple different cell types have the ability to accumulate lipid droplets, and thus we must evaluate the criteria with which we distinguish BMAds from other cells of the BM. In the context of extramedullary stromal differentiation, some groups have adopted the criteria of presence of at least four lipid droplets to define an adipocyte (165). This is especially useful as a threshold in imaging techniques where lipid droplets are visible ( Figures 4A,C,E).…”

Section: Bmad Differentiation Assessment: In Vitro Assays and Applicamentioning

confidence: 99%

Reporting Guidelines, Review of Methodological Standards, and Challenges Toward Harmonization in Bone Marrow Adiposity Research. Report of the Methodologies Working Group of the International Bone Marrow Adiposity Society

et al. 2020

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The interest in bone marrow adiposity (BMA) has increased over the last decade due to its association with, and potential role, in a range of diseases (osteoporosis, diabetes, anorexia, cancer) as well as treatments (corticosteroid, radiation, chemotherapy, thiazolidinediones). However, to advance the field of BMA research, standardization of methods is desirable to increase comparability of study outcomes and foster collaboration. Therefore, at the 2017 annual BMA meeting, the International Bone Marrow Adiposity Society (BMAS) founded a working group to evaluate methodologies in BMA research. All BMAS members could volunteer to participate. The working group members, who are all active preclinical or clinical BMA researchers, searched the literature for articles investigating BMA and discussed the results during personal and telephone conferences. According to the consensus opinion, both based on the review of the literature and on expert opinion, we describe existing methodologies and discuss the challenges and future directions for (1) histomorphometry of bone marrow adipocytes, (2) ex vivo BMA imaging, (3) in vivo BMA imaging, (4) cell isolation, culture, differentiation and in vitro modulation of primary bone marrow adipocytes and bone marrow stromal cell precursors, (5) lineage tracing and in vivo BMA modulation, and (6) BMA biobanking. We identify as accepted standards in BMA research: manual histomorphometry and osmium tetroxide 3D contrast-enhanced µCT for ex vivo quantification, specific MRI sequences (WFI and H-MRS) for in vivo studies, and RT-qPCR with a minimal four gene panel or lipid-based assays for in vitro quantification of bone marrow adipogenesis. Emerging techniques are described which may soon come to complement or substitute these gold standards. Known confounding factors and minimal reporting standards are presented, and their use is encouraged to facilitate comparison across studies. In conclusion, specific BMA methodologies have been developed. However, important challenges remain. In particular, we advocate for the harmonization of methodologies, the precise reporting of known confounding factors, and the identification of methods to modulate BMA independently from other tissues. Wider use of existing animal models with impaired BMA production (e.g., Pfrt −/− , Kit W/W−v) and development of specific BMA deletion models would be highly desirable for this purpose.

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Section: Bmad Differentiation Assessment: In Vitro Assays and Applicamentioning

confidence: 99%

Reporting Guidelines, Review of Methodological Standards, and Challenges Toward Harmonization in Bone Marrow Adiposity Research. Report of the Methodologies Working Group of the International Bone Marrow Adiposity Society

et al. 2020

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“…For example, we found 4 TFs (FOXM1, PBX3, ZKSCAN1, ZEB1) enriched in HDL and TG only, 4 TFs (EZH2, NFE2, NFATC1, KDM5A) enriched in HDL only and 11 TFs (FOSL1, IRF3, JUN, MEF2C, NANOG, PRDM1, RUNX3, SIRT6, SMC3, STAT3, ZNF217) enriched in TG only. Of these TFs, the central role of ZEB1 in adiposity 55 and fat cell differentiation has been demonstrated 56 .…”

Section: Overlapping Gwas Signals With Binding Sites Highlights Lipid-relevant Tfsmentioning

confidence: 99%

A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

Ramdas

Judd

Graham

et al. 2021

Preprint

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A major challenge of genome-wide association studies (GWAS) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations, and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels, and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. Two prioritized genes, CREBRF and RRBP1, show convergent evidence across functional datasets supporting their roles in lipid biology.

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Author response: Identification of the transcription factor ZEB1 as a central component of the adipogenic gene regulatory network

Cited by 2 publications

References 0 publications

Reporting Guidelines, Review of Methodological Standards, and Challenges Toward Harmonization in Bone Marrow Adiposity Research. Report of the Methodologies Working Group of the International Bone Marrow Adiposity Society

Reporting Guidelines, Review of Methodological Standards, and Challenges Toward Harmonization in Bone Marrow Adiposity Research. Report of the Methodologies Working Group of the International Bone Marrow Adiposity Society

A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

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