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FUNTIONAL SPECIFICITY AND EXPRESSION OF HUMAN HISTONE H1 VARIANTS
FUNTIONAL SPECIFICITY AND EXPRESSION OF HUMAN HISTONE H1 VARIANTS
Histone H1, also known as linker histone, is involved in the formation of higher-order chromatin structure, in the maintenance of nucleosome spacing, in the regulation of gene expression and in chromatin dynamics. In mammals, histone H1 is a multigene family that includes 7 somatic variants or subtypes (H1.0-H1.5 and H1x) and 4 germline-specific variants. Why there are so many H1 variants and whether are they redundant or have specific functions are questions still unanswered. However, we and other researchers have shown that H1 variants differ in several features including, chromatin-binding affinity, expression patterns, post-translational modifications, evolution velocities, genome-wide distribution and regulation of the expression of specific genes. All those evidences are in favor of the functional differentiation of H1 variants.
Histone H1, also known as linker histone, is involved in the formation of higher-order chromatin structure, in the maintenance of nucleosome spacing, in the regulation of gene expression and in chromatin dynamics. In mammals, histone H1 is a multigene family that includes 7 somatic variants or subtypes (H1.0-H1.5 and H1x) and 4 germline-specific variants. Why there are so many H1 variants and whether are they redundant or have specific functions are questions still unanswered. However, we and other researchers have shown that H1 variants differ in several features including, chromatin-binding affinity, expression patterns, post-translational modifications, evolution velocities, genome-wide distribution and regulation of the expression of specific genes. All those evidences are in favor of the functional differentiation of H1 variants.
Our working hypothesis is that H1 variants are functionally distinct. Therefore, we aim to understand the differences of H1 somatic variants in several aspects, including the variant-specific quantitative composition, the genome-wide distribution and the interaction with nuclear factors. We will also analyze the role of specific transcription factors, of the modifications of the mRNA bases and of the interaction between mRNA and specific RNA binding-proteins in establishing the expression patterns characteristic of H1 somatic variants.
Our working hypothesis is that H1 variants are functionally distinct. Therefore, we aim to understand the differences of H1 somatic variants in several aspects, including the variant-specific quantitative composition, the genome-wide distribution and the interaction with nuclear factors. We will also analyze the role of specific transcription factors, of the modifications of the mRNA bases and of the interaction between mRNA and specific RNA binding-proteins in establishing the expression patterns characteristic of H1 somatic variants.
We have found that the combined depletion of H1.2 and H1.4 induces changes at chromatin level and trigger inteferon response. Based on these results we will study how the combined depletion of different variants in several cell-types will affect gene expression, chromatin organization and genome stability, as well as their impact on innate immunity and programmed cell death. We will also study the presence of transcriptional and/or post-transcriptional compensatory effects resulting in changes in the protein levels of specific variants.
We have found that the combined depletion of H1.2 and H1.4 induces changes at chromatin level and trigger inteferon response. Based on these results we will study how the combined depletion of different variants in several cell-types will affect gene expression, chromatin organization and genome stability, as well as their impact on innate immunity and programmed cell death. We will also study the presence of transcriptional and/or post-transcriptional compensatory effects resulting in changes in the protein levels of specific variants.
A great number of studies have shown that quantitative alterations in H1 somatic variants are associated with cancer progression. For that reason, we propose to characterize the differences between normal and tumoral cells regarding the protein quantities and genome-wide distribution of the somatic H1 variants, as well as their effects in gene expression. In addition, we will study how the depletion of specific variants affects cancer progression and will also explore the possibility of using one or more somatic variants as biomarkers for the diagnosis and prognosis of leukemia.
A great number of studies have shown that quantitative alterations in H1 somatic variants are associated with cancer progression. For that reason, we propose to characterize the differences between normal and tumoral cells regarding the protein quantities and genome-wide distribution of the somatic H1 variants, as well as their effects in gene expression. In addition, we will study how the depletion of specific variants affects cancer progression and will also explore the possibility of using one or more somatic variants as biomarkers for the diagnosis and prognosis of leukemia.
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