Sp1 Regulates Chromatin Looping between an Intronic Enhancer and Distal Promoter of the Human Heme Oxygenase-1 Gene in Renal Cells

Deshane, Jessy; Kim, Jung-Hyun; Bolisetty, Subhashini; Hock, Thomas D.; Hill‐Kapturczak, Nathalie; Agarwal, Anupam

doi:10.1074/jbc.m109.058586

Cited by 59 publications

(57 citation statements)

References 50 publications

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“…Among promoters with decreased H3K4me3 in SLE, we saw enrichment of STAT1 and CEBPB as well as enrichment of PU.1, SP1, IRF1, BLIMP1, IRF8 and STAT6. PU.1 is another pioneer transcription factor and SP1 is associated with chromatin looping [58]. BLIMP1, a monocyte differentiation factor, was previously identified by us as associated with increased H4 acetylation peaks in SLE [23,37].…”

Section: Discussionmentioning

confidence: 99%

Monocyte Enhancers are Highly Altered in Systemic Lupus Erythematosus

et al. 2015

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Objective: Histone modifications set transcriptional competency and can perpetuate pathologic expression patterns. We defined systemic lupus erythematosus (SLE)-specific changes in H3K4me3 and K3K27me3, histone marks of gene activation and repression, respectively. Methods: We used ChIP-seq to define histone modifications in monocytes from SLE patients and controls. Results: Both promoters and enhancers exhibited significant changes in histone methylation in SLE. Regions with differential H3K4me3 in SLE were significantly enriched in potential interferon-related transcription factor binding sites and pioneer transcription factor sites. Conclusion: Enhancer activation defines the character of the cell and our data support extensive disease effects in monocytes, a particularly plastic lineage. Type I interferons not only drive altered gene expression but may also alter the character of the cell through chromatin modifications.

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Section: Discussionmentioning

confidence: 99%

Monocyte Enhancers are Highly Altered in Systemic Lupus Erythematosus

et al. 2015

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“…This technique can be used to inhibit target genes regulated by a transcriptional activator or to induce target genes regulated by a transcriptional repressor. 33 Recent studies have shown that ODN decoys against NF-B, 19 Sp1, 20 STAT, 34 and E2F 35 were able to modulate the transcription of their downstream target genes both in cell cultures and in animal models. Our studies using the ZNF24 decoy confirm the 11-bp fragment as the binding site for ZNF24 and raise the possibility of using this ODN decoy to regulate VEGF in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…19,20 Because our studies demonstrated that the 11-bp fragment of the proximal VEGF promoter serves as ZNF24-binding site, we next investigated whether the Ϫ150/Ϫ128 promoter region containing the 11-bp fragment could regulate VEGF expression in cells when used as ODN decoys for ZNF24. Cotransfection of the VEGF promoter ODN completely abolished the repression of the VEGF promoter by ZNF24, in contrast to the scrambled ODN, which did not affect the repression ( Figure 2F).…”

Section: -Bp Fragment Of the Vegf Promoter Mediates Vegf Transcriptionmentioning

confidence: 99%

Transcriptional repression of VEGF by ZNF24: mechanistic studies and vascular consequences in vivo

Jia

Hasso

Chan

et al. 2013

Blood

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Key Points• ZNF24 represses VEGF transcription through direct binding to an 11-bp fragment of the VEGF proximal promoter.• ZNF24 functions as a negative regulator of developmental and tumor angiogenesis by inhibiting VEGF transcription.VEGF is a key regulator of normal and pathologic angiogenesis. Although many trans-activating factors of VEGF have been described, the transcriptional repression of VEGF remains much less understood. We have previously reported the identification of a SCAN domain-containing C2H2 zinc finger protein, ZNF24, that represses the transcription of VEGF. In the present study, we identify the mechanism by which ZNF24 represses VEGF transcription. Using reporter gene and electrophoretic mobility shift assays, we identify an 11-bp fragment of the proximal VEGF promoter as the ZNF24-binding site that is essential for ZNF24-mediated repression. We demonstrate in 2 in vivo models the potent inhibitory effect of ZNF24 on the vasculature. Expression of human ZNF24 induced in vivo vascular defects consistent with those induced by VEGF knockdown using a transgenic zebrafish model. These defects could be rescued by VEGF overexpression. Overexpression of ZNF24 in human breast cancer cells also inhibited tumor angiogenesis in an in vivo tumor model. Analyses of human breast cancer tissues showed that ZNF24 and VEGF levels were inversely correlated in malignant compared with normal tissues. These data demonstrate that ZNF24 represses VEGF transcription through direct binding to an 11-bp fragment of the VEGF proximal promoter and that it functions as a negative IntroductionVEGF is a key angiogenic factor during embryogenesis, as demonstrated by the embryonic lethality and abnormal blood vessel development of mice lacking a single VEGF allele. 1 It also plays critical roles in normal physiologic processes such as maintaining vascular stability 2 and promoting skeletal muscle differentiation. 3 Across a wide range of human cancers, VEGF serves as a principle proangiogenic factor. For example, VEGF levels are elevated in breast cancer patients 4 and are inversely correlated with patient survival. 5 Transcriptional regulation of VEGF has been defined in part by its many transcriptional activators, including Sp1, HIF-1, and STAT3. 6,7 In contrast, only the p53 family proteins and the von Hippel-Lindau (VHL) tumor suppressor have been discovered and well characterized as transcriptional repressors of VEGF.Zinc finger protein 24 (ZNF24, also known as ZNF191 or Kox17) was originally identified in an attempt to discover novel C2H2 zinc finger proteins in the hematopoietic system. 8 It possesses 4 Kruppel-like C2H2 zinc finger domains within the c-terminus that function as DNA-binding domains. 9 These domains bind to the TCAT repeats of the HUMTH01 microsatellite located in the first intron of the tyrosine hydroxylase gene in in vitro studies. 9,10 No in vivo function relevant to this observation has been documented to date. The N-terminus of ZNF24 contains a SCAN box domain that primarily serves as a dimerizat...

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“…These sites include response elements for STATx, c-Rel, hepatocyte factor-1 and -4, and GATA-X (75,98,119,129,130,138). In human renal epithelial cells, an intronic enhancer controls HO-1 expression via chromatin looping and Sp1-dependent interaction with the -4.0 kb HO-1 promoter region (36).…”

Section: Fig 3 Ho Enzymatic Reactionmentioning

confidence: 99%