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Distinct DNA-based epigenetic switches trigger transcriptional activation of silent genes in human dermal fibroblasts (Affymetrix)

ABSTRACT: Artificial epigenetic switches are of increasing demand owing to the critical role of the dynamic epigenome in orchestrating genome-wide transcriptional activation. Recently, we divulged that certain epigenetically active small molecules called SAHA-PIPs containing the cell permeable pyrrole-imidazole polyamides (PIPs) as DNA recognition module and a histone deacetylases inhibitor SAHA as functional module, is capable of triggering targeted transcriptional activation of pluripotency and germ cell genes in mouse and human fibroblasts, respectively. Through microarray studies and functional analysis, here we demonstrate the first ever example about the remarkable ability of 32 different SAHA-PIPs to trigger transcriptional activation of their own unique set of genes and noncoding RNAs. QRT-PCR studies validated that certain SAHA-PIPs could induce several therapeutically important genes including KSR2 and SEMA6A to suggest its potential use as reagents capable of targeted transcriptional activation and as probe(s) to identify the functional relevance of the uncharacterized genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE53316 | GEO | 2013/12/31

SECONDARY ACCESSION(S): PRJNA231680

REPOSITORIES: GEO

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Project description:Cancer immunotherapy using monoclonal antibodies (mAbs) to immune checkpoint (e.g., PD-1) has revolutionized the cancer treatments with long-term clinical benefits and being applicable to a wide range of tumors. However, a significant fraction of cancer patients does not respond to PD-1 blockade-based monotherapy. Considering the potential of combinatorial therapies in overcoming existing limitations of cancer immunotherapy, there is an increasing need to identify small-molecule modulators of immune cells capable of augmenting the effect of PD-1 blockade, leading to better cancer treatment. Although epigenetic drugs have shown potential in combination therapy, the lack of sequence specificity is a major concern. Pyrrole–imidazole polyamide (PIP), a selective DNA-binding small molecule, can guide epigenetic modulators to enable targeted gene activation. Here, we prepared and screened a library of PIPs encompassing the distinct PIPs conjugated with P300/CBP-selective bromodomain inhibitor (BI), which acts as a P300/CBP recruiter, and identified a PIP called BI-PIP-R that can trigger the targeted induction of the peroxisome proliferator-activated receptor-gamma coactivator 1 alpha/beta (PGC-1a/b), a regulator of mitochondrial activation and biogenesis. We further improved the chemical architecture of BI-PIP-R using a tri-arginine vector for better nuclear accumulation. This designer dual-functional molecule termed EnPGC-1 that enhanced mitochondrial activation, energy metabolism, proliferation of CD8+ T cells in vitro, and, in particular, enhanced oxidative phosphorylation (OXPHOS), a feature of long-lived memory T cells. Genome-wide gene analysis also suggested that EnPGC-1 and not the control compounds can regulate T cell activation as a major biological process. EnPGC-1 also synergizes with PD-1 blockade that enhances antitumor immunity and improves the survival. Together, this study represents the first example of a programmable DNA-based epigenetic drug with the potential to overcome the existing issues in cancer immunotherapy.

Project description:Cancer immunotherapy using monoclonal antibodies (mAbs) to immune checkpoint (e.g., PD-1) has revolutionized the cancer treatments with long-term clinical benefits and being applicable to a wide range of tumors. However, a significant fraction of cancer patients does not respond to PD-1 blockade-based monotherapy. Considering the potential of combinatorial therapies in overcoming existing limitations of cancer immunotherapy, there is an increasing need to identify small-molecule modulators of immune cells capable of augmenting the effect of PD-1 blockade, leading to better cancer treatment. Although epigenetic drugs have shown potential in combination therapy, the lack of sequence specificity is a major concern. Pyrrole–imidazole polyamide (PIP), a selective DNA-binding small molecule, can guide epigenetic modulators to enable targeted gene activation. Here, we prepared and screened a library of PIPs encompassing the distinct PIPs conjugated with P300/CBP-selective bromodomain inhibitor (BI), which acts as a P300/CBP recruiter, and identified a PIP called BI-PIP-R that can trigger the targeted induction of the peroxisome proliferator-activated receptor-gamma coactivator 1 alpha/beta (PGC-1a/b), a regulator of mitochondrial activation and biogenesis. We further improved the chemical architecture of BI-PIP-R using a tri-arginine vector for better nuclear accumulation. This designer dual-functional molecule termed EnPGC-1 that enhanced mitochondrial activation, energy metabolism, proliferation of CD8+ T cells in vitro, and, in particular, enhanced oxidative phosphorylation (OXPHOS), a feature of long-lived memory T cells. Genome-wide gene analysis also suggested that EnPGC-1 and not the control compounds can regulate of T cell activation as a major biological process. EnPGC-1 also synergized with PD-1 blockade to enhance antitumor immunity and improved the survival. Together, this study represents the first example of a programmable DNA-based epigenetic drug with the potential to overcome the existing issues in cancer immunotherapy.

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Distinct DNA-based epigenetic switches trigger transcriptional activation of silent genes in human dermal fibroblasts (Affymetrix)

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