Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA369615 | ENA |
REPOSITORIES: ENA
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Project description:Targeting the HBZ Viral Oncoprotein Transcriptional Network in Adult T-cell leukemia/lymphoma (ChIP-Seq)
| PRJNA373891 | ENA
Project description:Adult T-cell Leukemia/Lymphoma (ATLL) is a frequently incurable disease associated with the human lymphotropic virus type I (HTLV-I). The transcription factor HBZ is the only virally encoded gene that is expressed in all ATLL cases, but it is unclear why it may be essential in ATLL and how it might be targeted therapeutically. Here we performed RNA interference screening of ATLL lines and discovered that their proliferation depends on the transcription factors BATF3 and IRF4, which regulate the identity of normal immune cells. These factors, which are highly expressed in ATLL, cooperatively bind and transactivate genes that distinguish ATLL from other T cell malignancies, including BATF3 itself. HBZ binds to an ATLL-specific BATF3 super-enhancer and thereby regulates the expression of BATF3 and its downstream targets, including the oncogene MYC. The BET protein inhibitor JQ1 collapsed the transcriptional network directed by HBZ and BATF3, and was consequently toxic for ATLL lines and patient samples in vitro, and blocked growth of ATLL xenografts. Our study demonstrates that the HTLV-I virus exploits a regulatory module that can potentially be attacked therapeutically with BET protein inhibitors.
2018-07-10 | GSE94409 | GEO
Project description:Adult T-cell Leukemia/Lymphoma (ATLL) is a frequently incurable disease associated with the human lymphotropic virus type I (HTLV-I). The transcription factor HBZ is the only virally encoded gene that is expressed in all ATLL cases, but it is unclear why it may be essential in ATLL and how it might be targeted therapeutically. Here we performed RNA interference screening of ATLL lines and discovered that their proliferation depends on the transcription factors BATF3 and IRF4, which regulate the identity of normal immune cells. These factors, which are highly expressed in ATLL, cooperatively bind and transactivate genes that distinguish ATLL from other T cell malignancies, including BATF3 itself. HBZ binds to an ATLL-specific BATF3 super-enhancer and thereby regulates the expression of BATF3 and its downstream targets, including the oncogene MYC. The BET protein inhibitor JQ1 collapsed the transcriptional network directed by HBZ and BATF3, and was consequently toxic for ATLL lines and patient samples in vitro, and blocked growth of ATLL xenografts. Our study demonstrates that the HTLV-I virus exploits a regulatory module that can potentially be attacked therapeutically with BET protein inhibitors.
2018-07-10 | GSE94732 | GEO
Project description:Human T-cell leukemia virus type 1 (HTLV-1) encodes HTLV-1 bZIP factor (HBZ), which is thought to be crucial for neoplastic and inflammatory diseases caused by HTLV-1. So, we analyzed the transcriptional profile of HBZ expressing cells and how HBZ affect the expression of apoptosis-related genes. We used microarrays to detail the effect of HTLV-1 bZIP factor (HBZ), which is encoded in the minus strand of HTLV-1 genome on gene expression. Especially how HBZ affect the expression of apoptosis-related genes. Jurkat cells stably expressing HBZ were stimulated with or without PMA and ionomycin for 9hours. Then RNA extraction and hybridization on Affymetrix microarrays were performed.
2013-06-18 | E-GEOD-48029 | biostudies-arrayexpress
Project description:Human T-cell leukemia virus type 1 (HTLV-1) encodes HTLV-1 bZIP factor (HBZ), which is thought to be crucial for neoplastic and inflammatory diseases caused by HTLV-1. So, we analyzed the transcriptional profile of HBZ expressing cells and how HBZ affect the expression of apoptosis-related genes. We used microarrays to detail the effect of HTLV-1 bZIP factor (HBZ), which is encoded in the minus strand of HTLV-1 genome on gene expression. Especially how HBZ affect the expression of apoptosis-related genes.
2013-06-18 | GSE48029 | GEO
Project description:The regulation of α-like globin gene expression, particularly the embryonic ζ-globin gene (HBZ), remains poorly understood compared to the well-characterized β-globin switch. To systematically identify transcriptional regulators of HBZ, we developed an HBZ-P2A-GFP reporter system in erythroid cell lines (K562 and HUDEP-2) and performed a CRISPR/Cas9 screen targeting 1,639 transcription factors. We identified SKI as a potent repressor of HBZ. Genetic ablation of SKI significantly upregulated HBZ without impairing erythropoiesis, whereas its overexpression suppressed HBZ. Inducible expression and degradation assays confirmed that SKI directly represses HBZ transcription. RNA-seq revealed that SKI deletion specifically activates HBZ with minimal effects on other erythroid genes. ChIP-seq demonstrated SKI binding at key distal enhancers (HS-10 and HS-40), partially overlapping with BCL11A. Dual knockout of SKI and BCL11A synergistically enhanced HBZ expression. Base editing of the SKI-binding site at HS-10 also increased HBZ expression, and a nearby natural variant (chr16:143207_G/A) was identified in α-thalassemia patients with elevated ζ-globin. Our findings establish SKI as a direct transcriptional repressor of HBZ and reveal a synergistic regulatory mechanism with BCL11A. This work provides new insights into globin gene regulation and suggests potential therapeutic strategies for α-thalassemia through targeted activation of ζ-globin.
2026-02-28 | GSE307347 | GEO
Project description:The regulation of α-like globin gene expression, particularly the embryonic ζ-globin gene (HBZ), remains poorly understood compared to the well-characterized β-globin switch. To systematically identify transcriptional regulators of HBZ, we developed an HBZ-P2A-GFP reporter system in erythroid cell lines (K562 and HUDEP-2) and performed a CRISPR/Cas9 screen targeting 1,639 transcription factors. We identified SKI as a potent repressor of HBZ. Genetic ablation of SKI significantly upregulated HBZ without impairing erythropoiesis, whereas its overexpression suppressed HBZ. Inducible expression and degradation assays confirmed that SKI directly represses HBZ transcription. RNA-seq revealed that SKI deletion specifically activates HBZ with minimal effects on other erythroid genes. ChIP-seq demonstrated SKI binding at key distal enhancers (HS-10 and HS-40), partially overlapping with BCL11A. Dual knockout of SKI and BCL11A synergistically enhanced HBZ expression. Base editing of the SKI-binding site at HS-10 also increased HBZ expression, and a nearby natural variant (chr16:143207_G/A) was identified in α-thalassemia patients with elevated ζ-globin. Our findings establish SKI as a direct transcriptional repressor of HBZ and reveal a synergistic regulatory mechanism with BCL11A. This work provides new insights into globin gene regulation and suggests potential therapeutic strategies for α-thalassemia through targeted activation of ζ-globin.
2026-02-28 | GSE307348 | GEO
Project description:The regulation of α-like globin gene expression, particularly the embryonic ζ-globin gene (HBZ), remains poorly understood compared to the well-characterized β-globin switch. To systematically identify transcriptional regulators of HBZ, we developed an HBZ-P2A-GFP reporter system in erythroid cell lines (K562 and HUDEP-2) and performed a CRISPR/Cas9 screen targeting 1,639 transcription factors. We identified SKI as a potent repressor of HBZ. Genetic ablation of SKI significantly upregulated HBZ without impairing erythropoiesis, whereas its overexpression suppressed HBZ. Inducible expression and degradation assays confirmed that SKI directly represses HBZ transcription. RNA-seq revealed that SKI deletion specifically activates HBZ with minimal effects on other erythroid genes. ChIP-seq demonstrated SKI binding at key distal enhancers (HS-10 and HS-40), partially overlapping with BCL11A. Dual knockout of SKI and BCL11A synergistically enhanced HBZ expression. Base editing of the SKI-binding site at HS-10 also increased HBZ expression, and a nearby natural variant (chr16:143207_G/A) was identified in α-thalassemia patients with elevated ζ-globin. Our findings establish SKI as a direct transcriptional repressor of HBZ and reveal a synergistic regulatory mechanism with BCL11A. This work provides new insights into globin gene regulation and suggests potential therapeutic strategies for α-thalassemia through targeted activation of ζ-globin.
2026-02-28 | GSE307350 | GEO
Project description:Five percent of HTLV-1 infected subjects develops an untreatable form of cancer designated Adult T cell leukemia (ATL). The HTLV-1-encoded HBZ protein is believed to act as a viral oncogene by disarranging crucial pathways in the infected cells. Key to thisfunction is a progressive cytoplasmic-to-nuclear dislocation of HBZ and its interaction with nuclear factors whose complexity wasnot assessed until now. In this investigation we unveiled for the first time such complexity by studying the endogenous HBZinteractome in a leukemic cell line derived from an ATL patient. A high number of nuclear interactors, represented by at least 249members, were found. Among the various family of interactors, we found predominant the family involved in RNA splicing and RNAstability. A disarrangement of the splicing mechanism was demonstrated both in ATL cells and in non HTLV-1-derived leukemic cellsexpressing HBZ after genetic transfer, strongly suggesting that a major mechanism leading to HTLV-1-mediated transformationand persistence of the oncogenic state is related to this event. Our unprecedented results shed new light on the mechanisms bywhich a human retrovirus can alter the infected cell metabolism and strongly predispose and/or maintain neoplastictransformation
2022-07-27 | GSE206085 | GEO