{"id":{"repo_id":"washington","oai_identifier":"oai:digital.lib.washington.edu:1773/53711"},"canonical_url":"https://search.dev.ndltd.org/etd/washington/oai:digital.lib.washington.edu:1773/53711","repository":{"repo_id":"washington","name":"University of Washington","base_url":"https://digital.lib.washington.edu/server/oai/request"},"display":{"title":"Before and after DUX4: deconstructing its web of silencers and defining its long-term impact on cellular processes","abstract":"Facioscapulohumeral dystrophy (FSHD) is driven by a loss of epigenetic repression at the D4Z4 repeat region, leading to aberrant expression of early embryonic transcription factor Double Homeobox 4 (DUX4) and an embryonic transcriptional program in skeletal muscle. Mechanisms that initiate and maintain epigenetic repression at the D4Z4 are complex and incompletely understood. Here, I designed a functional silencing reporter system to identify specific D4Z4 sequences that drive silencing activity and discovered that one discrete sequence, termed D4Z4-S5, was sufficient for sequence-dependent silencer recruitment. This sequence drives silencing activity through both de novo DNA methylation and repressive histone modifications, driven specifically by several previously identified D4Z4 silencers: SETDB1, ATF7IP, SIN3A/3B, and LRIF1. The reporter system also showed promise as a robust platform for further discovery of FSHD therapeutics and disease modifiers, with candidate therapeutic p38 pathway inhibitors showing increased repression in D4Z4-S5. Our findings identify a key D4Z4 regulatory sequence that drives epigenetic repression and proposes a novel system for further screening of FSHD disease modifiers and therapeutics. The second focus of this work is based on the long-term effects of DUX4 in cancer. Expression of DUX4 has been identified in a wide variety of solid tissue cancers. DUX4 was recently found to be a driver of immune evasion and is associated with poor prognosis in response to immune-mediated cancer therapies due to a loss of antigen presentation machinery. Though the transcriptional activity of DUX4 has been well characterized, recent studies have implicated DUX4 in post-transcriptional modulation of cellular processes. Here, I describe the mechanism of DUX4-mediated translational suppression, leading to translational reprogramming. I also describe optimization attempts to develop a DUX4-lineage tracing system for further study of long-term effects of DUX4 activity in cancer and FSHD.","abstract_html":"Facioscapulohumeral dystrophy (FSHD) is driven by a loss of epigenetic repression at the D4Z4 repeat region, leading to aberrant expression of early embryonic transcription factor Double Homeobox 4 (DUX4) and an embryonic transcriptional program in skeletal muscle. Mechanisms that initiate and maintain epigenetic repression at the D4Z4 are complex and incompletely understood. Here, I designed a functional silencing reporter system to identify specific D4Z4 sequences that drive silencing activity and discovered that one discrete sequence, termed D4Z4-S5, was sufficient for sequence-dependent silencer recruitment. This sequence drives silencing activity through both de novo DNA methylation and repressive histone modifications, driven specifically by several previously identified D4Z4 silencers: SETDB1, ATF7IP, SIN3A/3B, and LRIF1. The reporter system also showed promise as a robust platform for further discovery of FSHD therapeutics and disease modifiers, with candidate therapeutic p38 pathway inhibitors showing increased repression in D4Z4-S5. Our findings identify a key D4Z4 regulatory sequence that drives epigenetic repression and proposes a novel system for further screening of FSHD disease modifiers and therapeutics. The second focus of this work is based on the long-term effects of DUX4 in cancer. Expression of DUX4 has been identified in a wide variety of solid tissue cancers. DUX4 was recently found to be a driver of immune evasion and is associated with poor prognosis in response to immune-mediated cancer therapies due to a loss of antigen presentation machinery. Though the transcriptional activity of DUX4 has been well characterized, recent studies have implicated DUX4 in post-transcriptional modulation of cellular processes. Here, I describe the mechanism of DUX4-mediated translational suppression, leading to translational reprogramming. I also describe optimization attempts to develop a DUX4-lineage tracing system for further study of long-term effects of DUX4 activity in cancer and FSHD.","abstract_has_math":false,"creators":["Paatela, Ellen"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Tapscott, Stephen J"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-08-01","date_published":"2025-08-01","updated_at":"2026-07-24T05:58:07Z","subjects":["DUX4","Epigenetic Regulation","FSHD","Post-Transcriptional Regulation","Molecular biology","Cellular biology","Genetics"],"languages":["en_US"],"rights":["none"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/1773/53711","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Tapscott, Stephen J"]},{"key":"dc:creator","label":"Author","values":["Paatela, Ellen"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-08-01T22:28:02Z"]},{"key":"dc:date.issued","label":"Date","values":["2025-08-01"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["DUX4","Epigenetic Regulation","FSHD","Post-Transcriptional Regulation","Molecular biology","Cellular biology","Genetics"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en_US"]},{"key":"dc:rights","label":"Dc Rights","values":["none"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["Paatela_washington_0250E_28350.pdf"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/1773/53711"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Thesis (Ph.D.)--University of Washington, 2025"]},{"key":"dc:description.abstract","label":"Abstract","values":["Facioscapulohumeral dystrophy (FSHD) is driven by a loss of epigenetic repression at the D4Z4 repeat region, leading to aberrant expression of early embryonic transcription factor Double Homeobox 4 (DUX4) and an embryonic transcriptional program in skeletal muscle. Mechanisms that initiate and maintain epigenetic repression at the D4Z4 are complex and incompletely understood. Here, I designed a functional silencing reporter system to identify specific D4Z4 sequences that drive silencing activity and discovered that one discrete sequence, termed D4Z4-S5, was sufficient for sequence-dependent silencer recruitment. This sequence drives silencing activity through both de novo DNA methylation and repressive histone modifications, driven specifically by several previously identified D4Z4 silencers: SETDB1, ATF7IP, SIN3A/3B, and LRIF1. The reporter system also showed promise as a robust platform for further discovery of FSHD therapeutics and disease modifiers, with candidate therapeutic p38 pathway inhibitors showing increased repression in D4Z4-S5. Our findings identify a key D4Z4 regulatory sequence that drives epigenetic repression and proposes a novel system for further screening of FSHD disease modifiers and therapeutics. The second focus of this work is based on the long-term effects of DUX4 in cancer. Expression of DUX4 has been identified in a wide variety of solid tissue cancers. DUX4 was recently found to be a driver of immune evasion and is associated with poor prognosis in response to immune-mediated cancer therapies due to a loss of antigen presentation machinery. Though the transcriptional activity of DUX4 has been well characterized, recent studies have implicated DUX4 in post-transcriptional modulation of cellular processes. Here, I describe the mechanism of DUX4-mediated translational suppression, leading to translational reprogramming. I also describe optimization attempts to develop a DUX4-lineage tracing system for further study of long-term effects of DUX4 activity in cancer and FSHD."]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Before and after DUX4: deconstructing its web of silencers and defining its long-term impact on cellular processes"]}]}],"canonical_facts":{"dc:contributor.advisor":["Tapscott, Stephen J"],"dc:creator":["Paatela, Ellen"],"dc:date.accessioned":["2025-08-01T22:28:02Z"],"dc:date.issued":["2025-08-01"],"dc:description":["Thesis (Ph.D.)--University of Washington, 2025"],"dc:description.abstract":["Facioscapulohumeral dystrophy (FSHD) is driven by a loss of epigenetic repression at the D4Z4 repeat region, leading to aberrant expression of early embryonic transcription factor Double Homeobox 4 (DUX4) and an embryonic transcriptional program in skeletal muscle. Mechanisms that initiate and maintain epigenetic repression at the D4Z4 are complex and incompletely understood. Here, I designed a functional silencing reporter system to identify specific D4Z4 sequences that drive silencing activity and discovered that one discrete sequence, termed D4Z4-S5, was sufficient for sequence-dependent silencer recruitment. This sequence drives silencing activity through both de novo DNA methylation and repressive histone modifications, driven specifically by several previously identified D4Z4 silencers: SETDB1, ATF7IP, SIN3A/3B, and LRIF1. The reporter system also showed promise as a robust platform for further discovery of FSHD therapeutics and disease modifiers, with candidate therapeutic p38 pathway inhibitors showing increased repression in D4Z4-S5. Our findings identify a key D4Z4 regulatory sequence that drives epigenetic repression and proposes a novel system for further screening of FSHD disease modifiers and therapeutics. The second focus of this work is based on the long-term effects of DUX4 in cancer. Expression of DUX4 has been identified in a wide variety of solid tissue cancers. DUX4 was recently found to be a driver of immune evasion and is associated with poor prognosis in response to immune-mediated cancer therapies due to a loss of antigen presentation machinery. Though the transcriptional activity of DUX4 has been well characterized, recent studies have implicated DUX4 in post-transcriptional modulation of cellular processes. Here, I describe the mechanism of DUX4-mediated translational suppression, leading to translational reprogramming. I also describe optimization attempts to develop a DUX4-lineage tracing system for further study of long-term effects of DUX4 activity in cancer and FSHD."],"dc:format.mimetype":["application/pdf"],"dc:identifier.other":["Paatela_washington_0250E_28350.pdf"],"dc:identifier.uri":["https://hdl.handle.net/1773/53711"],"dc:language.iso":["en_US"],"dc:rights":["none"],"dc:subject":["DUX4","Epigenetic Regulation","FSHD","Post-Transcriptional Regulation","Molecular biology","Cellular biology","Genetics"],"dc:title":["Before and after DUX4: deconstructing its web of silencers and defining its long-term impact on cellular processes"],"dc:type":["Thesis"]},"updated_at":"2026-07-24T05:58:07Z"}