The central role of creatine and polyamines in fetal growth restriction.

Placental insufficiency often correlates with fetal growth restriction (FGR), a condition that has both short- and long-term effects on the health of the newborn. In our study, we analyzed placental tissue from infants with FGR and from infants classified as small for gestational age (SGA) or appropriate for gestational age (AGA), performing comprehensive analyses that included transcriptomics and metabolomics. By examining villus tissue biopsies and 3D trophoblast organoids, we identified significant metabolic changes in placentas associated with FGR.

T-regulatory cells require Sin3a for stable expression of Foxp3.

Histone deacetylases 1 and 2 play a major role in the transcriptional regulation of T-regulatory (Treg) cells via interactions with a myriad of coregulatory factors. Sin3a has been well established as a Hdac1/2 cofactor, while its role within Tregs has not been established. In this study, the effects of conditional deletion of Sin3a within Foxp3+ Tregs were evaluated.

HDAC4 influences the DNA damage response and counteracts senescence by assembling with HDAC1/HDAC2 to control H2BK120 acetylation and homology-directed repair.

Access to DNA is the first level of control in regulating gene transcription, a control that is also critical for maintaining DNA integrity. Cellular senescence is characterized by profound transcriptional rearrangements and accumulation of DNA lesions. Here, we discovered an epigenetic complex between HDAC4 and HDAC1/HDAC2 that is involved in the erase of H2BK120 acetylation.

Folding of Class IIa HDAC Derived Peptides into α-helices Upon Binding to Myocyte Enhancer Factor-2 in Complex with DNA.

Interaction of transcription factor myocyte enhancer factor-2 (MEF2) family members with class IIa histone deacetylases (HDACs) has been implicated in a wide variety of diseases. Though considerable knowledge on this topic has been accumulated over the years, a high resolution and detailed analysis of the binding mode of multiple class IIa HDAC derived peptides with MEF2D is still lacking. To fulfil this gap, we report here the crystal structure of MEF2D in complex with double strand DNA and four different class IIa HDAC derived peptides, namely HDAC4, HDAC5, HDAC7 and HDAC9.

Changes in chromatin accessibility and transcriptional landscape induced by HDAC inhibitors in TP53 mutated patient-derived colon cancer organoids.

Here we present the generation and characterization of patient-derived organoids (PDOs) from colorectal cancer patients. PDOs derived from two patients with TP53 mutations were tested with two different HDAC inhibitors (SAHA and NKL54). Cell death induction, transcriptome, and chromatin accessibility changes were analyzed.

Transcription of endogenous retroviruses in senescent cells contributes to the accumulation of double-stranded RNAs that trigger an anti-viral response that reinforces senescence.

An important epigenetic switch marks the onset and maintenance of senescence. This allows transcription of the genetic programs that arrest the cell cycle and alter the microenvironment. Transcription of endogenous retroviruses (ERVs) is also a consequence of this epigenetic switch.

Suppression of the - axis shifts arginine into the phosphocreatine energy system in pancreatic cancer cells.

In pancreatic ductal adenocarcinomas (PDAC), the axis controls cellular functions such as redox homeostasis and metabolism. Disruption of this axis through suppression of leads to profound reprogramming of metabolism. Unbiased transcriptome and metabolome analyses showed that PDAC cells with disrupted signaling ( cells) shift from aerobic glycolysis to metabolic pathways fed by amino acids.

NRF2 interacts with distal enhancer and inhibits nitric oxide synthase 2 expression in KRAS-driven pancreatic cancer cells.

Nitric oxide is a pleiotropic free radical produced by three nitric oxide synthases (NOS1-3), of which inducible NOS2 is involved in tumor initiation and progression. In this study, RNA-seq, ChIP-seq and qRT-PCR experiments combined with bioinformatic analyses showed that NRF2 is a repressor of NOS2 gene by maintaining a distal enhancer located 22 kb downstream of TSS in an inactive state. Deletion of NRF2 leads to activation of the enhancer, which exerts a pioneering function before it is fully activated.

Dual-targeting peptides@PMO, a mimetic to the pro-apoptotic protein Smac/DIABLO for selective activation of apoptosis in cancer cells.

The refractoriness of tumor cells to apoptosis represents the main mechanism of resistance to chemotherapy. Smac/DIABLO mimetics proved to be effective in overcoming cancer-acquired resistance to apoptosis as a consequence of overexpression of the anti-apoptotic proteins XIAP, cIAP1, and cIAP2. In this work, we describe a dual-targeting peptide capable of selectively activating apoptosis in cancer cells.

Super-enhancer landscape rewiring in cancer: The epigenetic control at distal sites.

Super-enhancers evolve as elements at the top of the hierarchical control of gene expression. They are important end-gatherers of signaling pathways that control stemness, differentiation or adaptive responses. Many epigenetic regulations focus on these regions, and not surprisingly, during the process of tumorigenesis, various alterations can account for their dysfunction.

Endogenous Retroviruses (ERVs): Does RLR (RIG-I-Like Receptors)-MAVS Pathway Directly Control Senescence and Aging as a Consequence of ERV De-Repression?

Bi-directional transcription of Human Endogenous Retroviruses (hERVs) is a common feature of autoimmunity, neurodegeneration and cancer. Higher rates of cancer incidence, neurodegeneration and autoimmunity but a lower prevalence of autoimmune diseases characterize elderly people. Although the re-expression of hERVs is commonly observed in different cellular models of senescence as a result of the loss of their epigenetic transcriptional silencing, the hERVs modulation during aging is more complex, with a peak of activation in the sixties and a decline in the nineties.

Photosensitization of pancreatic cancer cells by cationic alkyl-porphyrins in free form or engrafted into POPC liposomes: The relationship between delivery mode and mechanism of cell death.

Cationic porphyrins bearing an alkyl side chain of 14 (2b) or 18 (2d) carbons dramatically inhibit proliferation of pancreatic cancer cells following treatment with light. We have compared two different ways of delivering porphyrin 2d: either in free form or engrafted into palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine liposomes (L-2d). Cell cytometry shows that while free 2d is taken up by pancreatic cancer cells by active (endocytosis) and passive (membrane fusion) transports, L-2d is internalized solely by endocytosis.

Transcriptomic and genomic studies classify NKL54 as a histone deacetylase inhibitor with indirect influence on MEF2-dependent transcription.

In leiomyosarcoma class IIa HDACs (histone deacetylases) bind MEF2 and convert these transcription factors into repressors to sustain proliferation. Disruption of this complex with small molecules should antagonize cancer growth. NKL54, a PAOA (pimeloylanilide o-aminoanilide) derivative, binds a hydrophobic groove of MEF2, which is used as a docking site by class IIa HDACs.

A Biological Circuit Involving Mef2c, Mef2d, and Hdac9 Controls the Immunosuppressive Functions of CD4+Foxp3+ T-Regulatory Cells.

The Mads/Mef2 (Mef2a/b/c/d) family of transcription factors (TFs) regulates differentiation of muscle cells, neurons and hematopoietic cells. By functioning in physiological feedback loops, Mef2 TFs promote the transcription of their repressor, Hdac9, thereby providing temporal control of Mef2-driven differentiation. Disruption of this feedback is associated with the development of various pathologic states, including cancer.

HDAC4 degradation during senescence unleashes an epigenetic program driven by AP-1/p300 at selected enhancers and super-enhancers.

Background: Cellular senescence is a permanent state of replicative arrest defined by a specific pattern of gene expression. The epigenome in senescent cells is sculptured in order to sustain the new transcriptional requirements, particularly at enhancers and super-enhancers. How these distal regulatory elements are dynamically modulated is not completely defined.

A regulative epigenetic circuit supervised by HDAC7 represses IGFBP6 and IGFBP7 expression to sustain mammary stemness.

In the breast, the pleiotropic epigenetic regulator HDAC7 can influence stemness. The authors used MCF10 cells knocked-out for HDAC7 to explore the contribution of HDAC7 to IGF1 signaling. HDAC7 buffers H3K27ac levels at the IGFBP6 and IGFBP7 genomic loci and influences their expression.

Enhancing Proteotoxic Stress in Leiomyosarcoma Cells Triggers Mitochondrial Dysfunctions, Cell Death, and Antitumor Activity .

Leiomyosarcomas are rare and aggressive tumors characterized by a complex karyotype. Surgical resection with or without radiotherapy and chemotherapy is the standard curative treatment. Unfortunately, a high percentage of leiomyosarcomas recurs and metastasizes.

Quis Custodiet Ipsos Custodes (Who Controls the Controllers)? Two Decades of Studies on HDAC9.

Understanding how an epigenetic regulator drives different cellular responses can be a tricky task. Very often, their activities are modulated by large multiprotein complexes, the composition of which is context- and time-dependent. As a consequence, experiments aimed to unveil the functions of an epigenetic regulator can provide different outcomes and conclusions, depending on the circumstances.

MEF2D sustains activation of effector Foxp3+ Tregs during transplant survival and anticancer immunity.

The transcription factor MEF2D is important in the regulation of differentiation and adaptive responses in many cell types. We found that among T cells, MEF2D gained new functions in Foxp3+ T regulatory (Treg) cells due to its interactions with the transcription factor Foxp3 and its release from canonical partners, like histone/protein deacetylases. Though not necessary for the generation and maintenance of Tregs, MEF2D was required for the expression of IL-10, CTLA4, and Icos, and for the acquisition of an effector Treg phenotype.

The Histone Code of Senescence.

Senescence is the end point of a complex cellular response that proceeds through a set of highly regulated steps. Initially, the permanent cell-cycle arrest that characterizes senescence is a pro-survival response to irreparable DNA damage. The maintenance of this prolonged condition requires the adaptation of the cells to an unfavorable, demanding and stressful microenvironment.

GSK3β is a key regulator of the ROS-dependent necrotic death induced by the quinone DMNQ.

Signaling pathways controlling necrosis are still mysterious and debated. We applied a shRNA-based viability screen to identify critical elements of the necrotic response. We took advantage from a small molecule (G5) that makes covalent adducts with free thiols by Michael addition and elicits multiple stresses.

Inhibiting the coregulator CoREST impairs Foxp3+ Treg function and promotes antitumor immunity.

Foxp3+ Tregs are key to immune homeostasis, but the contributions of various large, multiprotein complexes that regulate gene expression remain unexplored. We analyzed the role in Tregs of the evolutionarily conserved CoREST complex, consisting of a scaffolding protein, Rcor1 or Rcor2, plus Hdac1 or Hdac2 and Lsd1 enzymes. Rcor1, Rcor2, and Lsd1 were physically associated with Foxp3, and mice with conditional deletion of Rcor1 in Foxp3+ Tregs had decreased proportions of Tregs in peripheral lymphoid tissues and increased Treg expression of IL-2 and IFN-γ compared with what was found in WT cells.

Genetic Programs Driving Oncogenic Transformation: Lessons from in Vitro Models.

Cancer complexity relies on the intracellular pleiotropy of oncogenes/tumor suppressors and in the strong interplay between tumors and micro- and macro-environments. Here we followed a reductionist approach, by analyzing the transcriptional adaptations induced by three oncogenes (, , and ) in an isogenic transformation process. Common pathways, in place of common genes became dysregulated.