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Assessment of human health risks from exposure to ionizing radiation (IR) is mainly based on the extrapolation of results from epidemiological studies on populations exposed to relatively high doses and often at high dose rates (HDR). Risk estimates after exposure to low doses and in particular at low dose rates (LDR) remain controversial due to a lack of epidemiological evidence. Therefore, high priority is given to strengthening the evidence on which risk assessments can be based for low doses and LDR. It is known that the cytotoxicity of radiation decreases by decreasing dose rate. Less is known about the effects of LDR on mutation rates and premature senescence compared to HDR. We established 2 cell lines with low expression of two proteins, MTH1 or MYH, both involved in the protection of cells from mutation induction by reactive oxygen species (ROS). The cells were exposed to different doses at different dose rates, and the levels of mutation were studied. The results showed a possible dose-rate threshold for mutations for the MTH1/MYH double knockdown cells. Next, we studied the effect of dose rate on adaptive response (AR). AR is defined as the ability of a low dose of ionizing radiation to induce enhanced resistance in cells subsequently exposed to a high dose. We established dose response relations for survival and mutations for MCF-10A cells exposed/non-exposed to an adaptive dose of 50 mGy at different dose rates, followed by exposure to different high doses. We found no protective effect of 50 mGy on survival. However, we observed that 50 mGy the adaptive dose reduced the mutation frequency induced by 1 Gy challenging dose. The protection level was higher when 50 mGy was delivered at LDR. A significant amount of data suggests that oxidative stress, induced for example by LDR, can contribute to senescence. We cultured VH10 cells, beginning with passage 13, during chronic LDR exposure. The cells were passaged every week for 6 weeks until they stopped proli

Assessment of human health risks from exposure to ionizing radiation (IR) is mainly based on the extrapolation of results from epidemiological studies on populations exposed to relatively high doses and often at high dose rates (HDR). Risk estimates after exposure to low doses and in particular at low dose rates (LDR) remain controversial due to a lack of epidemiological evidence. Therefore, high priority is given to strengthening the evidence on which risk assessments can be based for low doses and LDR. It is known that the cytotoxicity of radiation decreases by decreasing dose rate. Less is known about the effects of LDR on mutation rates and premature senescence compared to HDR. We established 2 cell lines with low expression of two proteins, MTH1 or MYH, both involved in the protection of cells from mutation induction by reactive oxygen species (ROS). The cells were exposed to different doses at different dose rates, and the levels of mutation were studied. The results showed a possible dose-rate threshold for mutations for the MTH1/MYH double knockdown cells. Next, we studied the effect of dose rate on adaptive response (AR). AR is defined as the ability of a low dose of ionizing radiation to induce enhanced resistance in cells subsequently exposed to a high dose. We established dose response relations for survival and mutations for MCF-10A cells exposed/non-exposed to an adaptive dose of 50 mGy at different dose rates, followed by exposure to different high doses. We found no protective effect of 50 mGy on survival. However, we observed that 50 mGy the adaptive dose reduced the mutation frequency induced by 1 Gy challenging dose. The protection level was higher when 50 mGy was delivered at LDR. A significant amount of data suggests that oxidative stress, induced for example by LDR, can contribute to senescence. We cultured VH10 cells, beginning with passage 13, during chronic LDR exposure. The cells were passaged every week for 6 weeks until they stopped proli

Assessment of human health risks from exposure to ionizing radiation (IR) is mainly based on the extrapolation of results from epidemiological studies on populations exposed to relatively high doses and often at high dose rates (HDR). Risk estimates after exposure to low doses and in particular at low dose rates (LDR) remain controversial due to a lack of epidemiological evidence. Therefore, high priority is given to strengthening the evidence on which risk assessments can be based for low doses and LDR. It is known that the cytotoxicity of radiation decreases by decreasing dose rate. Less is known about the effects of LDR on mutation rates and premature senescence compared to HDR. We established 2 cell lines with low expression of two proteins, MTH1 or MYH, both involved in the protection of cells from mutation induction by reactive oxygen species (ROS). The cells were exposed to different doses at different dose rates, and the levels of mutation were studied. The results showed a possible dose-rate threshold for mutations for the MTH1/MYH double knockdown cells. Next, we studied the effect of dose rate on adaptive response (AR). AR is defined as the ability of a low dose of ionizing radiation to induce enhanced resistance in cells subsequently exposed to a high dose. We established dose response relations for survival and mutations for MCF-10A cells exposed/non-exposed to an adaptive dose of 50 mGy at different dose rates, followed by exposure to different high doses. We found no protective effect of 50 mGy on survival. However, we observed that 50 mGy the adaptive dose reduced the mutation frequency induced by 1 Gy challenging dose. The protection level was higher when 50 mGy was delivered at LDR. A significant amount of data suggests that oxidative stress, induced for example by LDR, can contribute to senescence. We cultured VH10 cells, beginning with passage 13, during chronic LDR exposure. The cells were passaged every week for 6 weeks until they stopped proli

Assessment of human health risks from exposure to ionizing radiation (IR) is mainly based on the extrapolation of results from epidemiological studies on populations exposed to relatively high doses and often at high dose rates (HDR). Risk estimates after exposure to low doses and in particular at low dose rates (LDR) remain controversial due to a lack of epidemiological evidence. Therefore, high priority is given to strengthening the evidence on which risk assessments can be based for low doses and LDR. It is known that the cytotoxicity of radiation decreases by decreasing dose rate. Less is known about the effects of LDR on mutation rates and premature senescence compared to HDR. We established 2 cell lines with low expression of two proteins, MTH1 or MYH, both involved in the protection of cells from mutation induction by reactive oxygen species (ROS). The cells were exposed to different doses at different dose rates, and the levels of mutation were studied. The results showed a possible dose-rate threshold for mutations for the MTH1/MYH double knockdown cells. Next, we studied the effect of dose rate on adaptive response (AR). AR is defined as the ability of a low dose of ionizing radiation to induce enhanced resistance in cells subsequently exposed to a high dose. We established dose response relations for survival and mutations for MCF-10A cells exposed/non-exposed to an adaptive dose of 50 mGy at different dose rates, followed by exposure to different high doses. We found no protective effect of 50 mGy on survival. However, we observed that 50 mGy the adaptive dose reduced the mutation frequency induced by 1 Gy challenging dose. The protection level was higher when 50 mGy was delivered at LDR. A significant amount of data suggests that oxidative stress, induced for example by LDR, can contribute to senescence. We cultured VH10 cells, beginning with passage 13, during chronic LDR exposure. The cells were passaged every week for 6 weeks until they stopped proli

Assessment of human health risks from exposure to ionizing radiation (IR) is mainly based on the extrapolation of results from epidemiological studies on populations exposed to relatively high doses and often at high dose rates (HDR). Risk estimates after exposure to low doses and in particular at low dose rates (LDR) remain controversial due to a lack of epidemiological evidence. Therefore, high priority is given to strengthening the evidence on which risk assessments can be based for low doses and LDR. It is known that the cytotoxicity of radiation decreases by decreasing dose rate. Less is known about the effects of LDR on mutation rates and premature senescence compared to HDR. We established 2 cell lines with low expression of two proteins, MTH1 or MYH, both involved in the protection of cells from mutation induction by reactive oxygen species (ROS). The cells were exposed to different doses at different dose rates, and the levels of mutation were studied. The results showed a possible dose-rate threshold for mutations for the MTH1/MYH double knockdown cells. Next, we studied the effect of dose rate on adaptive response (AR). AR is defined as the ability of a low dose of ionizing radiation to induce enhanced resistance in cells subsequently exposed to a high dose. We established dose response relations for survival and mutations for MCF-10A cells exposed/non-exposed to an adaptive dose of 50 mGy at different dose rates, followed by exposure to different high doses. We found no protective effect of 50 mGy on survival. However, we observed that 50 mGy the adaptive dose reduced the mutation frequency induced by 1 Gy challenging dose. The protection level was higher when 50 mGy was delivered at LDR. A significant amount of data suggests that oxidative stress, induced for example by LDR, can contribute to senescence. We cultured VH10 cells, beginning with passage 13, during chronic LDR exposure. The cells were passaged every week for 6 weeks until they stopped proli

Assessment of human health risks from exposure to ionizing radiation (IR) is mainly based on the extrapolation of results from epidemiological studies on populations exposed to relatively high doses and often at high dose rates (HDR). Risk estimates after exposure to low doses and in particular at low dose rates (LDR) remain controversial due to a lack of epidemiological evidence. Therefore, high priority is given to strengthening the evidence on which risk assessments can be based for low doses and LDR. It is known that the cytotoxicity of radiation decreases by decreasing dose rate. Less is known about the effects of LDR on mutation rates and premature senescence compared to HDR. We established 2 cell lines with low expression of two proteins, MTH1 or MYH, both involved in the protection of cells from mutation induction by reactive oxygen species (ROS). The cells were exposed to different doses at different dose rates, and the levels of mutation were studied. The results showed a possible dose-rate threshold for mutations for the MTH1/MYH double knockdown cells. Next, we studied the effect of dose rate on adaptive response (AR). AR is defined as the ability of a low dose of ionizing radiation to induce enhanced resistance in cells subsequently exposed to a high dose. We established dose response relations for survival and mutations for MCF-10A cells exposed/non-exposed to an adaptive dose of 50 mGy at different dose rates, followed by exposure to different high doses. We found no protective effect of 50 mGy on survival. However, we observed that 50 mGy the adaptive dose reduced the mutation frequency induced by 1 Gy challenging dose. The protection level was higher when 50 mGy was delivered at LDR. A significant amount of data suggests that oxidative stress, induced for example by LDR, can contribute to senescence. We cultured VH10 cells, beginning with passage 13, during chronic LDR exposure. The cells were passaged every week for 6 weeks until they stopped proli

During cell specification, temporal and spatially restricted gene expression programs are set up, forming different cell types and ultimately a multicellular organism. In this thesis, we have studied the molecular mechanisms by which sequence specific transcription factors and coactivators regulate RNA polymerase II (Pol II) transcription to establish specific gene expression programs and what epigenetic patterns that follows. We found that the transcription factor Dorsal is responsible for establishing discrete epigenetic patterns in the presumptive mesoderm, neuroectoderm and dorsal ectoderm, during early Drosophila embryo development. In addition, these different chromatin states can be linked to distinct modes of Pol II regulation. Our results provide novel insights into how gene regulatory networks form an epigenetic landscape and how their coordinated actions specify cell identity. CBP/p300 is a widely used co-activator and histone acetyltransferase (HAT) involved in transcriptional activation. We discovered that CBP occupies the genome preferentially together with Dorsal, and has a specific role during development in coordinating the dorsal-ventral axis of the Drosophila embryo. While CBP generally correlates with gene activation we also found CBP in H3K27me3 repressed chromatin. Previous studies have shown that CBP has an important role at transcriptional enhancers. We provide evidence that the regulatory role of CBP does not stop at enhancers, but is extended to many genomic regions. CBP binds to insulators and regulates their activity by acetylating histones to prevent spreading of H3K27me3. We further discovered that CBP has a direct regulatory role at promoters. Using a highly potent CBP inhibitor in combination with ChIP and PRO-seq we found that CBP regulates promoter proximal pausing of Pol II. CBP promotes Pol II recruitment to promoters via a direct interaction with TFIIB, and promotes transcriptional elongation by acetylating the first nucleosome., At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

During cell specification, temporal and spatially restricted gene expression programs are set up, forming different cell types and ultimately a multicellular organism. In this thesis, we have studied the molecular mechanisms by which sequence specific transcription factors and coactivators regulate RNA polymerase II (Pol II) transcription to establish specific gene expression programs and what epigenetic patterns that follows. We found that the transcription factor Dorsal is responsible for establishing discrete epigenetic patterns in the presumptive mesoderm, neuroectoderm and dorsal ectoderm, during early Drosophila embryo development. In addition, these different chromatin states can be linked to distinct modes of Pol II regulation. Our results provide novel insights into how gene regulatory networks form an epigenetic landscape and how their coordinated actions specify cell identity. CBP/p300 is a widely used co-activator and histone acetyltransferase (HAT) involved in transcriptional activation. We discovered that CBP occupies the genome preferentially together with Dorsal, and has a specific role during development in coordinating the dorsal-ventral axis of the Drosophila embryo. While CBP generally correlates with gene activation we also found CBP in H3K27me3 repressed chromatin. Previous studies have shown that CBP has an important role at transcriptional enhancers. We provide evidence that the regulatory role of CBP does not stop at enhancers, but is extended to many genomic regions. CBP binds to insulators and regulates their activity by acetylating histones to prevent spreading of H3K27me3. We further discovered that CBP has a direct regulatory role at promoters. Using a highly potent CBP inhibitor in combination with ChIP and PRO-seq we found that CBP regulates promoter proximal pausing of Pol II. CBP promotes Pol II recruitment to promoters via a direct interaction with TFIIB, and promotes transcriptional elongation by acetylating the first nucleosome., At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

During cell specification, temporal and spatially restricted gene expression programs are set up, forming different cell types and ultimately a multicellular organism. In this thesis, we have studied the molecular mechanisms by which sequence specific transcription factors and coactivators regulate RNA polymerase II (Pol II) transcription to establish specific gene expression programs and what epigenetic patterns that follows. We found that the transcription factor Dorsal is responsible for establishing discrete epigenetic patterns in the presumptive mesoderm, neuroectoderm and dorsal ectoderm, during early Drosophila embryo development. In addition, these different chromatin states can be linked to distinct modes of Pol II regulation. Our results provide novel insights into how gene regulatory networks form an epigenetic landscape and how their coordinated actions specify cell identity. CBP/p300 is a widely used co-activator and histone acetyltransferase (HAT) involved in transcriptional activation. We discovered that CBP occupies the genome preferentially together with Dorsal, and has a specific role during development in coordinating the dorsal-ventral axis of the Drosophila embryo. While CBP generally correlates with gene activation we also found CBP in H3K27me3 repressed chromatin. Previous studies have shown that CBP has an important role at transcriptional enhancers. We provide evidence that the regulatory role of CBP does not stop at enhancers, but is extended to many genomic regions. CBP binds to insulators and regulates their activity by acetylating histones to prevent spreading of H3K27me3. We further discovered that CBP has a direct regulatory role at promoters. Using a highly potent CBP inhibitor in combination with ChIP and PRO-seq we found that CBP regulates promoter proximal pausing of Pol II. CBP promotes Pol II recruitment to promoters via a direct interaction with TFIIB, and promotes transcriptional elongation by acetylating the first nucleosome., At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

During cell specification, temporal and spatially restricted gene expression programs are set up, forming different cell types and ultimately a multicellular organism. In this thesis, we have studied the molecular mechanisms by which sequence specific transcription factors and coactivators regulate RNA polymerase II (Pol II) transcription to establish specific gene expression programs and what epigenetic patterns that follows. We found that the transcription factor Dorsal is responsible for establishing discrete epigenetic patterns in the presumptive mesoderm, neuroectoderm and dorsal ectoderm, during early Drosophila embryo development. In addition, these different chromatin states can be linked to distinct modes of Pol II regulation. Our results provide novel insights into how gene regulatory networks form an epigenetic landscape and how their coordinated actions specify cell identity. CBP/p300 is a widely used co-activator and histone acetyltransferase (HAT) involved in transcriptional activation. We discovered that CBP occupies the genome preferentially together with Dorsal, and has a specific role during development in coordinating the dorsal-ventral axis of the Drosophila embryo. While CBP generally correlates with gene activation we also found CBP in H3K27me3 repressed chromatin. Previous studies have shown that CBP has an important role at transcriptional enhancers. We provide evidence that the regulatory role of CBP does not stop at enhancers, but is extended to many genomic regions. CBP binds to insulators and regulates their activity by acetylating histones to prevent spreading of H3K27me3. We further discovered that CBP has a direct regulatory role at promoters. Using a highly potent CBP inhibitor in combination with ChIP and PRO-seq we found that CBP regulates promoter proximal pausing of Pol II. CBP promotes Pol II recruitment to promoters via a direct interaction with TFIIB, and promotes transcriptional elongation by acetylating the first nucleosome., At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

During cell specification, temporal and spatially restricted gene expression programs are set up, forming different cell types and ultimately a multicellular organism. In this thesis, we have studied the molecular mechanisms by which sequence specific transcription factors and coactivators regulate RNA polymerase II (Pol II) transcription to establish specific gene expression programs and what epigenetic patterns that follows. We found that the transcription factor Dorsal is responsible for establishing discrete epigenetic patterns in the presumptive mesoderm, neuroectoderm and dorsal ectoderm, during early Drosophila embryo development. In addition, these different chromatin states can be linked to distinct modes of Pol II regulation. Our results provide novel insights into how gene regulatory networks form an epigenetic landscape and how their coordinated actions specify cell identity. CBP/p300 is a widely used co-activator and histone acetyltransferase (HAT) involved in transcriptional activation. We discovered that CBP occupies the genome preferentially together with Dorsal, and has a specific role during development in coordinating the dorsal-ventral axis of the Drosophila embryo. While CBP generally correlates with gene activation we also found CBP in H3K27me3 repressed chromatin. Previous studies have shown that CBP has an important role at transcriptional enhancers. We provide evidence that the regulatory role of CBP does not stop at enhancers, but is extended to many genomic regions. CBP binds to insulators and regulates their activity by acetylating histones to prevent spreading of H3K27me3. We further discovered that CBP has a direct regulatory role at promoters. Using a highly potent CBP inhibitor in combination with ChIP and PRO-seq we found that CBP regulates promoter proximal pausing of Pol II. CBP promotes Pol II recruitment to promoters via a direct interaction with TFIIB, and promotes transcriptional elongation by acetylating the first nucleosome., At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

During cell specification, temporal and spatially restricted gene expression programs are set up, forming different cell types and ultimately a multicellular organism. In this thesis, we have studied the molecular mechanisms by which sequence specific transcription factors and coactivators regulate RNA polymerase II (Pol II) transcription to establish specific gene expression programs and what epigenetic patterns that follows. We found that the transcription factor Dorsal is responsible for establishing discrete epigenetic patterns in the presumptive mesoderm, neuroectoderm and dorsal ectoderm, during early Drosophila embryo development. In addition, these different chromatin states can be linked to distinct modes of Pol II regulation. Our results provide novel insights into how gene regulatory networks form an epigenetic landscape and how their coordinated actions specify cell identity. CBP/p300 is a widely used co-activator and histone acetyltransferase (HAT) involved in transcriptional activation. We discovered that CBP occupies the genome preferentially together with Dorsal, and has a specific role during development in coordinating the dorsal-ventral axis of the Drosophila embryo. While CBP generally correlates with gene activation we also found CBP in H3K27me3 repressed chromatin. Previous studies have shown that CBP has an important role at transcriptional enhancers. We provide evidence that the regulatory role of CBP does not stop at enhancers, but is extended to many genomic regions. CBP binds to insulators and regulates their activity by acetylating histones to prevent spreading of H3K27me3. We further discovered that CBP has a direct regulatory role at promoters. Using a highly potent CBP inhibitor in combination with ChIP and PRO-seq we found that CBP regulates promoter proximal pausing of Pol II. CBP promotes Pol II recruitment to promoters via a direct interaction with TFIIB, and promotes transcriptional elongation by acetylating the first nucleosome., At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.