{"lab": {"uuid": "fedfc81d-f1ce-4203-9c87-bc0b6eb2bfc3", "@type": ["Lab", "Item"], "@id": "/labs/golnaz-vahedi-lab/", "correspondence": [{"contact_email": "dmFoZWRpQHBlbm5tZWRpY2luZS51cGVubi5lZHU=", "@id": "/users/a44efbbf-7993-4258-b1ed-88045387e8ba/", "display_title": "Golnaz Vahedi"}], "title": "Golnaz Vahedi, UPENN", "status": "current", "display_title": "Golnaz Vahedi, UPENN", "pi": {"error": "no view permissions"}, "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin", "role.lab_submitter", "submits_for.fedfc81d-f1ce-4203-9c87-bc0b6eb2bfc3"]}}, "award": {"display_title": "SINGLE-CELL DISSECTION OF CHROMATIN ARCHITECTURE MECHANISMS CONNECTING PATHOLOGIC INSTABILITY AND TRANSCRIPTIONAL SILENCING", "name": "1U01DA052715-01", "project": "4DN", "description": "OFHHD: Short tandem repeat regions (STR) are distributed evenly across the human genome, and recent genome-wide studies have demonstrated that STRs are polymorphic across individuals and linked to gene expression levels. STR instability at key genomic loci has been causally linked to disease pathophysiology in a range of expansion disorders. We recently demonstrated that nearly all disease-associated STRs co-localize with boundaries demarcating topologically associated domains (TADs). Moreover, we have observed that pathologic STR instability and transcriptional silencing can destroy the associated boundary and shift genomic loci to the nuclear periphery. These results now open critical unanswered questions regarding whether and how STR expansion and pathologic alterations in gene expression are functionally linked to boundary integrity and radial positioning. Here, we focus on the prototypic repeat expansion disorder Friedreich\u2019s ataxia (FRDA) in which expansion of a GAA STR in the first intron of the FRATAXIN (FXN) gene results in cardiac and neuronal pathology. The cardiac pathology, specifically hypertrophy, fibrosis, and occasional dilation of the ventricle, is the etiology of significant FRDA mortality. GAA expansion is associated with the silencing of FXN transcription and a repositioning of the locus to the nuclear periphery. However, it remains unclear if the change in genome folding, radial positioning, or reduced expression drives STR expansion or vice versa. A major technical barrier contributing to this knowledge gap is that STR instability and genome folding are classically evaluated in bulk populations, however they exhibit tremendous variation across individual somatic cells of the same subtype and among cell types within a pathologically affected tissue. Here, we seek to decipher the causal link among STR instability, transcription, radial positioning, and genome folding. Our central hypothesis is that disruption of long-range loops is the initial event triggered by STR expansion leading to a cascade of heterochromatin spreading, silencing, and loss of radial positioning. We will test our hypothesis by generating genome-wide, single-cell maps of chromatin accessibility, expression, and the repressive H3K9me3 heterochromatin mark in GAA-expanded and control iPS cells and iPS-derived cardiomyocytes. We will integrate genomics data with single-cell sequential Oligopaints/OligoSTORM imaging of TADs and local chromatin structure, as well as single molecule RNA FISH for FXN expression. We will implement multiple genome engineering strategies, including dCas9-VP64 FXN activation and dCas9-CTCF loop re-engineering in FRDA GAA-iPS cells, and dCas9-Krab-Dnmt3a FXN silencing and dCas9-Krab CTCF-mediated loop disruption in healthy iPS cells. We will assay the effect of genome engineering approaches on TADs, radial positioning, STR length, and FXN expression in single cells. Successful completion of the proposed work will shed light on the pathophysiological mechanisms underlying repeat expansion disorders by deciphering the cause-and-effect relationships among genome folding, radial positioning, transcription, and STR expansion.", "@id": "/awards/1U01DA052715-01/", "@type": ["Award", "Item"], "uuid": "8c9d595e-2809-4779-ae6e-305341f695ff", "status": "current", "center_title": "OFHHD - Phillips-Cremins", "pi": {"error": "no view permissions"}, "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "badges": [{"badge": {"badge_classification": "Warning", "status": "released", "warning": "Replicate Numbers", "uuid": "24a64a84-3c33-4d76-aaf2-e5ef45eff347", "description": "Issues with replicate numbers", "@id": "/badges/replicate-numbers/", "title": "Replicate Numbers", "display_title": "Replicate Numbers", "badge_icon": "/static/img/badges/replicates-orange-circle.svg", "@type": ["Badge", "Item"], "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "messages": ["Replicate set contains only a single biological replicate"]}], "status": "released", "aliases": ["golnaz-vahedi-lab:expset_multiplexedfish_ets1"], "accession": "4DNESTTO3H2N", "condition": "WT DP T-cells", "description": "Multiplexed FISH (ORCA) in wild-type double positive (DP) T-cells derived from C57BL-6 mice to target Ets1-Fli1 locus", "date_created": "2024-06-03T20:20:14.868872+00:00", "submitted_by": {"error": "no view permissions"}, "dataset_label": "Multiplexed FISH DP T-cells mice", "last_modified": {"modified_by": {"error": "no view permissions"}, "date_modified": "2025-04-21T17:32:02.053387+00:00"}, "public_release": "2025-02-26", "replicate_exps": [{"bio_rep_no": 1, "tec_rep_no": 1, "replicate_exp": {"status": "released", "@id": "/experiments-mic/4DNEXSTYC535/", "@type": ["ExperimentMic", "Experiment", "Item"], "uuid": "d6b6ce37-c978-4005-9c2d-72406cf6dfad", "accession": "4DNEXSTYC535", "display_title": "multiplexed FISH on double-positive, alpha-beta thymocyte - 4DNEXSTYC535", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}}], "schema_version": "2", "static_headers": [{"lab": {"status": "current", "@type": ["Lab", "Item"], "display_title": "4DN DCIC, HMS", "@id": "/labs/4dn-dcic-lab/", "uuid": "828cd4fe-ebb0-4b36-a94a-d2e3a36cc989", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin", "role.lab_submitter", "submits_for.828cd4fe-ebb0-4b36-a94a-d2e3a36cc989"]}}, "body": "\n**Data Use Guidelines:** This is a data set generated by the \n4DN Network and made freely available to the scientific \ncommunity. If you are intending to use these data for a \npublication, we ask that you please contact the data \ngenerating lab to discuss possible coordinated publication. \nIn your manuscript, please cite the 4DN White Paper \n([doi:10.1038/nature23884](https://doi.org/10.1038/nature23884)) \nand the 4DN Data Portal paper \n([doi:10.1038/s41467-022-29697-4](https://doi.org/10.1038/s41467-022-29697-4)), \nand please acknowledge the 4DN lab which generated the data. Please direct any questions to the [Data Coordination and Integration Center](mailto:support@4dnucleome.org).", "name": "item-page-headers.ExperimentSet.data-usage-guidelines", "award": {"status": "current", "@type": ["Award", "Item"], "@id": "/awards/1U01CA200059-01/", "uuid": "b0b9c607-f8b4-4f02-93f4-9895b461334b", "display_title": "4D NUCLEOME NETWORK DATA COORDINATION AND INTEGRATION CENTER - PHASE I", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "title": "Data Usage Guidelines", "status": "released", "aliases": [], "options": {"filetype": "md", "title_icon": "exclamation-circle", "collapsible": false, "default_open": true}, "date_created": "2018-08-06T03:09:55.543206+00:00", "section_type": "Item Page Header", "submitted_by": {"error": "no view permissions"}, "last_modified": {"modified_by": {"error": "no view permissions"}, "date_modified": "2022-05-09T09:31:34.537494+00:00"}, "schema_version": "2", "@id": "/static-sections/621e8359-3885-40ce-965d-91894aa7b758/", "@type": ["StaticSection", "UserContent", "Item"], "uuid": "621e8359-3885-40ce-965d-91894aa7b758", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin", "role.owner", "userid.986b362f-4eb6-4a9c-8173-3ab267228139"]}, "display_title": "Data Usage Guidelines", "external_references": [], "content": "\n**Data Use Guidelines:** This is a data set generated by the \n4DN Network and made freely available to the scientific \ncommunity. If you are intending to use these data for a \npublication, we ask that you please contact the data \ngenerating lab to discuss possible coordinated publication. \nIn your manuscript, please cite the 4DN White Paper \n([doi:10.1038/nature23884](https://doi.org/10.1038/nature23884)) \nand the 4DN Data Portal paper \n([doi:10.1038/s41467-022-29697-4](https://doi.org/10.1038/s41467-022-29697-4)), \nand please acknowledge the 4DN lab which generated the data. Please direct any questions to the [Data Coordination and Integration Center](mailto:support@4dnucleome.org).", "filetype": "md", "content_as_html": "<div class=\"markdown-container\"><p><strong>Data Use Guidelines:</strong> This is a data set generated by the \n4DN Network and made freely available to the scientific \ncommunity. If you are intending to use these data for a \npublication, we ask that you please contact the data \ngenerating lab to discuss possible coordinated publication. \nIn your manuscript, please cite the 4DN White Paper \n(<a href=\"https://doi.org/10.1038/nature23884\" rel=\"noopener noreferrer\" target=\"_blank\">doi:10.1038/nature23884</a>) \nand the 4DN Data Portal paper \n(<a href=\"https://doi.org/10.1038/s41467-022-29697-4\" rel=\"noopener noreferrer\" target=\"_blank\">doi:10.1038/s41467-022-29697-4</a>), \nand please acknowledge the 4DN lab which generated the data. Please direct any questions to the <a href=\"mailto:support@4dnucleome.org\">Data Coordination and Integration Center</a>.</p></div>"}, {"lab": {"status": "current", "@type": ["Lab", "Item"], "display_title": "4DN DCIC, HMS", "@id": "/labs/4dn-dcic-lab/", "uuid": "828cd4fe-ebb0-4b36-a94a-d2e3a36cc989", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin", "role.lab_submitter", "submits_for.828cd4fe-ebb0-4b36-a94a-d2e3a36cc989"]}}, "body": "Processed files in this dataset are provided in the 4DN standard FISH-Omics Format - Chromatin Tracing (FOF-CT).\n\nThis is a collection of tabular files, consisting of several tables.\nThe DNA-spot/trace core table is organized around individual DNA bright Spots that are spatially linked together in a three-dimensional (3D) polymeric Trace.\nAdditional optional tables can complement this information and vary according to the specific dataset. \n\nThe full documentation is available here: https://fish-omics-format.readthedocs.io/", "name": "fof-ct.note", "award": {"status": "current", "@type": ["Award", "Item"], "@id": "/awards/2U01CA200059-06/", "uuid": "71171a4e-dca1-44cb-8375-fafd896c6923", "display_title": "4D NUCLEOME NETWORK DATA COORDINATION AND INTEGRATION CENTER - PHASE II", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "title": "Note on FOF-CT file format", "status": "released", "aliases": ["4dn-dcic-lab:fof_ct_note"], "options": {"filetype": "md", "collapsible": true, "default_open": false}, "date_created": "2022-03-07T18:23:27.469177+00:00", "section_type": "Item Page Header", "submitted_by": {"error": "no view permissions"}, "last_modified": {"modified_by": {"error": "no view permissions"}, "date_modified": "2022-03-08T14:28:37.893086+00:00"}, "schema_version": "2", "@id": "/static-sections/a09a2833-b56b-4e81-8eff-bb8ae6aaa596/", "@type": ["StaticSection", "UserContent", "Item"], "uuid": "a09a2833-b56b-4e81-8eff-bb8ae6aaa596", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin", "role.owner", "userid.e4a22298-1da4-4e59-8a65-9e661f47fb48"]}, "display_title": "Note on FOF-CT file format", "external_references": [], "content": "Processed files in this dataset are provided in the 4DN standard FISH-Omics Format - Chromatin Tracing (FOF-CT).\n\nThis is a collection of tabular files, consisting of several tables.\nThe DNA-spot/trace core table is organized around individual DNA bright Spots that are spatially linked together in a three-dimensional (3D) polymeric Trace.\nAdditional optional tables can complement this information and vary according to the specific dataset. \n\nThe full documentation is available here: https://fish-omics-format.readthedocs.io/", "filetype": "md", "content_as_html": "<div class=\"markdown-container\"><p>Processed files in this dataset are provided in the 4DN standard FISH-Omics Format - Chromatin Tracing (FOF-CT).</p>\n<p>This is a collection of tabular files, consisting of several tables.\nThe DNA-spot/trace core table is organized around individual DNA bright Spots that are spatially linked together in a three-dimensional (3D) polymeric Trace.\nAdditional optional tables can complement this information and vary according to the specific dataset. </p>\n<p>The full documentation is available here: https://fish-omics-format.readthedocs.io/</p></div>"}], "project_release": "2025-02-26", "experiments_in_set": [{"status": "released", "@type": ["ExperimentMic", "Experiment", "Item"], "uuid": "d6b6ce37-c978-4005-9c2d-72406cf6dfad", "display_title": "multiplexed FISH on double-positive, alpha-beta thymocyte - 4DNEXSTYC535", "@id": "/experiments-mic/4DNEXSTYC535/", "accession": "4DNEXSTYC535", "processed_files": [{"open_data_url": "https://4dn-open-data-public.s3.amazonaws.com/fourfront-webprod/wfoutput/9698686a-f41a-4977-ad49-9551206905b2/4DNFI5OF5LWK.csv", "file_size": 6009102, "genome_assembly": "GRCm38", "upload_key": "9698686a-f41a-4977-ad49-9551206905b2/4DNFI5OF5LWK.csv", "href": "/files-processed/4DNFI5OF5LWK/@@download/4DNFI5OF5LWK.csv", "display_title": "4DNFI5OF5LWK.csv", "accession": "4DNFI5OF5LWK", "md5sum": "f19d128aa1eb04dfcb9bfce759f7fccf", "@id": "/files-processed/4DNFI5OF5LWK/", "uuid": "9698686a-f41a-4977-ad49-9551206905b2", "file_format": {"status": "released", "uuid": "d13d06cf-218e-4f61-55f0-94f336118b2c", "@id": "/file-formats/csv/", "display_title": "csv", "@type": ["FileFormat", "Item"], "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "file_type": "FOF-CT - DNA-spot/trace core", "file_classification": "processed file", "file_type_detailed": "FOF-CT - DNA-spot/trace core (csv)", "status": "released", "@type": ["FileProcessed", "File", "Item"], "lab": {"name": "golnaz-vahedi-lab", "@id": "/labs/golnaz-vahedi-lab/", "uuid": "fedfc81d-f1ce-4203-9c87-bc0b6eb2bfc3", "status": "current", "@type": ["Lab", "Item"], "display_title": "Golnaz Vahedi, UPENN", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin", "role.lab_submitter", "submits_for.fedfc81d-f1ce-4203-9c87-bc0b6eb2bfc3"]}}, "last_modified": {"date_modified": "2025-04-14T15:56:57.249448+00:00"}, "track_and_facet_info": {"experimental_lab": "Golnaz Vahedi, UPENN", "experiment_type": "multiplexed FISH", "experiment_bucket": "processed file", "assay_info": "Ets1 mouse gene", "dataset": "Multiplexed FISH DP T-cells mice", "condition": "WT DP T-cells", "replicate_info": "Biorep 1, Techrep 1", "biosource_name": "double-positive, alpha-beta thymocyte", "lab_name": "Golnaz Vahedi, UPENN"}, "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}, "external_references": []}, {"open_data_url": "https://4dn-open-data-public.s3.amazonaws.com/fourfront-webprod/wfoutput/217d4336-f4d0-4f17-ac7d-80b15b7d6852/4DNFIMPCT3OK.csv", "file_size": 7931479, "genome_assembly": "GRCm38", "upload_key": "217d4336-f4d0-4f17-ac7d-80b15b7d6852/4DNFIMPCT3OK.csv", "href": "/files-processed/4DNFIMPCT3OK/@@download/4DNFIMPCT3OK.csv", "display_title": "4DNFIMPCT3OK.csv", "accession": "4DNFIMPCT3OK", "md5sum": "6ffc41213e1d260fd28447fa6211e55e", "@id": "/files-processed/4DNFIMPCT3OK/", "uuid": "217d4336-f4d0-4f17-ac7d-80b15b7d6852", "file_format": {"status": "released", "uuid": "d13d06cf-218e-4f61-55f0-94f336118b2c", "@id": "/file-formats/csv/", "display_title": "csv", "@type": ["FileFormat", "Item"], "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "file_type": "FOF-CT - spot quality", "file_classification": "processed file", "file_type_detailed": "FOF-CT - spot quality (csv)", "status": "released", "@type": ["FileProcessed", "File", "Item"], "lab": {"name": "golnaz-vahedi-lab", "@id": "/labs/golnaz-vahedi-lab/", "uuid": "fedfc81d-f1ce-4203-9c87-bc0b6eb2bfc3", "status": "current", "@type": ["Lab", "Item"], "display_title": "Golnaz Vahedi, UPENN", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin", "role.lab_submitter", "submits_for.fedfc81d-f1ce-4203-9c87-bc0b6eb2bfc3"]}}, "last_modified": {"date_modified": "2025-04-14T15:56:55.571046+00:00"}, "track_and_facet_info": {"experimental_lab": "Golnaz Vahedi, UPENN", "experiment_type": "multiplexed FISH", "experiment_bucket": "processed file", "assay_info": "Ets1 mouse gene", "dataset": "Multiplexed FISH DP T-cells mice", "condition": "WT DP T-cells", "replicate_info": "Biorep 1, Techrep 1", "biosource_name": "double-positive, alpha-beta thymocyte", "lab_name": "Golnaz Vahedi, UPENN"}, "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}, "external_references": []}], "biosample": {"status": "released", "display_title": "4DNBSDB4CAC8", "@type": ["Biosample", "Item"], "treatments_summary": "None", "@id": "/biosamples/4DNBSDB4CAC8/", "accession": "4DNBSDB4CAC8", "biosample_type": "primary cells", "modifications_summary": "None", "biosource_summary": "double-positive, alpha-beta thymocyte", "biosample_category": ["Other"], "uuid": "3851335b-07de-4e0a-8fac-256091912e19", "biosource": [{"cell_line_tier": "Unclassified", "@type": ["Biosource", "Item"], "@id": "/biosources/4DNSRNWQR9Y3/", "status": "released", "accession": "4DNSRNWQR9Y3", "biosource_type": "primary cell line", "uuid": "236b9e6f-184b-4eb4-b57f-5fc84e3a7dd5", "display_title": "double-positive, alpha-beta thymocyte - 4DNSRNWQR9Y3", "cell_line": {"term_name": "double-positive, alpha-beta thymocyte", "preferred_name": "double-positive, alpha-beta thymocyte", "@id": "/ontology-terms/CL:0000809/", "@type": ["OntologyTerm", "Item"], "display_title": "double-positive, alpha-beta thymocyte", "status": "released", "term_id": "CL:0000809", "uuid": "9f25a96e-97f9-46d5-b7eb-7964726bbcab", "synonyms": ["DP cell", "DP thymocyte", "double-positive, alpha-beta immature T lymphocyte"], "slim_terms": [{"status": "released", "@type": ["OntologyTerm", "Item"], "@id": "/ontology-terms/UBERON:0002370/", "display_title": "thymus", "uuid": "111179bc-8535-4448-903e-854af460a233", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, {"status": "released", "@type": ["OntologyTerm", "Item"], "@id": "/ontology-terms/UBERON:0002405/", "display_title": "immune system", "uuid": "111133bc-8535-4448-903e-854af460a233", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, {"status": "released", "@type": ["OntologyTerm", "Item"], "@id": "/ontology-terms/UBERON:0000949/", "display_title": "endocrine system", "uuid": "111126bc-8535-4448-903e-854af460a233", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, {"status": "released", "@type": ["OntologyTerm", "Item"], "@id": "/ontology-terms/UBERON:0000926/", "display_title": "mesoderm", "uuid": "111120bc-8535-4448-903e-854af460a233", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, {"status": "current", "@type": ["OntologyTerm", "Item"], "@id": "/ontology-terms/GO:0005623/", "display_title": "cell", "uuid": "72e16a19-eef3-46ca-a1b8-20e646e69675", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, {"status": "released", "@type": ["OntologyTerm", "Item"], "@id": "/ontology-terms/CL:0000000/", "display_title": "cell", "uuid": "45d2b02e-130b-40db-8bf2-2288c6c57dcf", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, {"status": "released", "@type": ["OntologyTerm", "Item"], "@id": "/ontology-terms/UBERON:0000925/", "display_title": "endoderm", "uuid": "111121bc-8535-4448-903e-854af460a233", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}], "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, "tissue": {"term_name": "thymus", "uuid": "111179bc-8535-4448-903e-854af460a233", "term_id": "UBERON:0002370", "preferred_name": "thymus", "@id": "/ontology-terms/UBERON:0002370/", "synonyms": ["thymus gland", "thymus organ"], "@type": ["OntologyTerm", "Item"], "status": "released", "display_title": "thymus", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}, "slim_terms": [{"@id": "/ontology-terms/UBERON:0000949/", "@type": ["OntologyTerm", "Item"], "display_title": "endocrine system", "uuid": "111126bc-8535-4448-903e-854af460a233", "status": "released", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, {"@id": "/ontology-terms/UBERON:0000925/", "@type": ["OntologyTerm", "Item"], "display_title": "endoderm", "uuid": "111121bc-8535-4448-903e-854af460a233", "status": "released", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, {"@id": "/ontology-terms/UBERON:0002370/", "@type": ["OntologyTerm", "Item"], "display_title": "thymus", "uuid": "111179bc-8535-4448-903e-854af460a233", "status": "released", "principals_allowed": {"view": ["system.Everyone"], "edit": ["group.admin"]}}, {"@id": 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In wild-type T cells, the predominant  chromatin conformation spatially links Ets1 to its proximal super-enhancer,  segregating Ets1 from Fli1 . This topology correlates with high Ets1 and low Fli1  expression. Deletion of the Ets1 super-enhancer abolishes this configuration,  triggering locus-wide architectural rewiring that increases Ets1-Fli1  promoter-promoter interactions and subsequently the co-expression of two genes  within individual cells. Remarkably, this compensatory interaction bypasses  insulated chromatin domains, sustaining Ets1 levels necessary for T cell  development despite enhancer loss. 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Deletion of the Ets1 super-enhancer abolishes this configuration,  triggering locus-wide architectural rewiring that increases Ets1-Fli1  promoter-promoter interactions and subsequently the co-expression of two genes  within individual cells. Remarkably, this compensatory interaction bypasses  insulated chromatin domains, sustaining Ets1 levels necessary for T cell  development despite enhancer loss. 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