Early B-cell Factor-1 (EBF1) Is a Key Regulator of Metabolic and Inflammatory Signaling Pathways in Mature Adipocytes

Griffin, Michael; Zhou, Yiming; Kang, Sona; Zhang, Xiaolan; Mikkelsen, Tarjei S.; Rosen, Evan D.

doi:10.1074/jbc.m113.491936

Cited by 44 publications

(38 citation statements)

References 48 publications

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“…A de novo search for enriched sequence motifs in these sites identified an EBF1-like binding motif as the most significantly enriched motif (Figure 3a), which was present in 78% of the identified binding regions. There was a clear enrichment of EBF1 binding sites in proximity to the transcriptional start site (TSS) of the nearest genes (Figure 3b), a distribution pattern, which is in line with previous findings in B-cells (Treiber et al, 2010) and more recently in 3T3-L1 cells (Griffin et al, 2013). In total, 2501 genes were identified as potential EBF1 target genes (Table S5) with the detected EBF1 binding region close to the respective TSS (±10 kb).…”

Section: Resultssupporting

confidence: 91%

“…Consistent with this, EBF1 , PPARG and CEBPA mRNA levels in WAT were lower in non-obese hypertrophy. As these three TFs cross-talk by regulating the expression of each other as well as similar target genes (Griffin et al, 2013), it is tempting to speculate that EBF1 reduction, with concomitant alterations in PPARγ and CEBPα levels, result in WAT hypertrophy via impaired fat cell differentiation. Because there are no established in vitro techniques to evaluate direct effects on morphology, the causal link between EBF1 down regulation and WAT hypertrophy was studied in Ebf1 +/− mice.…”

Section: Discussionmentioning

confidence: 99%

“…Recent work explored the effects of Ebf1 depletion by adenoviral shRNA in the immortalized murine cell line 3T3-L1 (Griffin et al, 2013). In analogy with our data, a significant but selective decrease in adipogenic genes such as Pparg and Cebpa was observed, without a global reduction of fat cell-enriched transcripts.…”

Section: Discussionmentioning

confidence: 99%

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Early B Cell Factor 1 Regulates Adipocyte Morphology and Lipolysis in White Adipose Tissue

et al. 2014

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Summary White adipose tissue (WAT) morphology characterized by hypertrophy (i.e. fewer but larger adipocytes) associates with increased adipose inflammation, lipolysis, insulin resistance and risk of diabetes. However, the causal relationships and the mechanisms controlling WAT morphology are unclear. Herein, we identified EBF1 as an adipocyte-expressed transcription factor with decreased expression/activity in WAT hypertrophy. In human adipocytes, the regulatory targets of EBF1 were enriched for genes controlling lipolysis and adipocyte morphology/differentiation and in both humans and murine models, reduced EBF1 levels associated with increased lipolysis and adipose hypertrophy. Although EBF1 did not affect adipose inflammation, TNFα reduced EBF1 gene expression. High fat diet-intervention in Ebf1+/− mice resulted in more pronounced WAT hypertrophy and attenuated insulin sensitivity compared with wild-type littermate controls. We conclude that EBF1 is an important regulator of adipose morphology and fat cell lipolysis and may constitute a link between WAT inflammation, altered lipid metabolism, adipose hypertrophy and insulin resistance.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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Early B Cell Factor 1 Regulates Adipocyte Morphology and Lipolysis in White Adipose Tissue

et al. 2014

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“…The Ebf1 shRNA vectors were reported previously by Griffin et al (2013). All hairpin sequences are in Supplemental Table S5.…”

Section: Knockdown Of Transcription Factors In Ikdn Pre-b Cells In Vitromentioning

confidence: 99%

Superenhancer reprogramming drives a B-cell–epithelial transition and high-risk leukemia

Zhang

Kashiwagi

et al. 2016

Genes Dev.

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IKAROS is required for the differentiation of highly proliferative pre-B-cell precursors, and loss of IKAROS function indicates poor prognosis in precursor B-cell acute lymphoblastic leukemia (B-ALL). Here we show that IKAROS regulates this developmental stage by positive and negative regulation of superenhancers with distinct lineage affiliations. IKAROS defines superenhancers at pre-B-cell differentiation genes together with B-cell master regulators such as PAX5, EBF1, and IRF4 but is required for a highly permissive chromatin environment, a function that cannot be compensated for by the other transcription factors. IKAROS is also highly enriched at inactive enhancers of genes normally expressed in stem-epithelial cells. Upon IKAROS loss, expression of pre-B-cell differentiation genes is attenuated, while a group of extralineage transcription factors that are directly repressed by IKAROS and depend on EBF1 relocalization at their enhancers for expression is induced. LHX2, LMO2, and TEAD-YAP1, normally kept separate from native B-cell transcription regulators by IKAROS, now cooperate directly with them in a de novo superenhancer network with its own feed-forward transcriptional reinforcement. Induction of de novo superenhancers antagonizes Polycomb repression and superimposes aberrant stem-epithelial cell properties in a B-cell precursor. This dual mechanism of IKAROS regulation promotes differentiation while safeguarding against a hybrid stem-epithelial-B-cell phenotype that underlies high-risk B-ALL.

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“…Although these results indicate that EBF1 is regulated by WAT inflammation and may have an impact on adipogenesis, further data suggest that other mechanisms may be involved as well. Indeed, in both humans and mice, EBF1 regulates basal (non-hormone-stimulated) fat-cell lipolysis by directly controlling the transcription of several key genes encoding lipolysis-regulating factors such as hormone-sensitive lipase and perilipin [6,7], resulting in an inverse relationship between EBF1 motif activity and lipolytic activity both in vivo and in vitro [6]. It is currently not known how adipose EBF1 expression/activity is related to different metabolic parameters.…”

Section: Introductionmentioning

confidence: 97%

Low early B-cell factor 1 (EBF1) activity in human subcutaneous adipose tissue is linked to a pernicious metabolic profile

Petrus

Mejhert

Gao

et al. 2015

Diabetes & Metabolism

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Early B-cell Factor-1 (EBF1) Is a Key Regulator of Metabolic and Inflammatory Signaling Pathways in Mature Adipocytes

Cited by 44 publications

References 48 publications

Early B Cell Factor 1 Regulates Adipocyte Morphology and Lipolysis in White Adipose Tissue

Early B Cell Factor 1 Regulates Adipocyte Morphology and Lipolysis in White Adipose Tissue

Superenhancer reprogramming drives a B-cell–epithelial transition and high-risk leukemia

Low early B-cell factor 1 (EBF1) activity in human subcutaneous adipose tissue is linked to a pernicious metabolic profile

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