Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1alpha) is a metabolic regulator of intestinal epithelial cell fate.

Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is a transcriptional coactivator able to up-regulate mitochondrial biogenesis, respiratory capacity, oxidative phosphorylation, and fatty acid ß-oxidation with the final aim of providing a more efficient pathway for aerobic energy production. In the continuously renewed intestinal epithelium, proliferative cells in the crypts migrate along the villus axis and differentiate into mature enterocytes, increasing their respiratory capacity and finally undergoing apoptosis. Here we show that in the intestinal epithelial surface, PGC1α drives mitochondrial biogenesis and respiration in the presence of reduced antioxidant enzyme activities, thus determining the accumulation of reactive oxygen species and fostering the fate of enterocytes toward apoptosis. Combining gain- and loss-of-function genetic approaches in human cells and mouse models of intestinal cancer, we present an intriguing scenario whereby PGC1α regulates enterocyte cell fate and protects against tumorigenesis.

Identification of a novel PPARß/δ/miR-21-3p axis in UV-induced skin inflammation.

Although excessive exposure to UV is widely recognized as a major factor leading to skin perturbations and cancer, the complex mechanisms underlying inflammatory skin disorders resulting from UV exposure remain incompletely characterized. The nuclear hormone receptor PPARß/δ is known to control mouse cutaneous repair and UV-induced skin cancer development. Here, we describe a novel PPARß/δ-dependent molecular cascade involving TGFß1 and miR-21-3p, which is activated in the epidermis in response to UV exposure. We establish that the passenger miRNA miR-21-3p, that we identify as a novel UV-induced miRNA in the epidermis, plays a pro-inflammatory function in keratinocytes and that its high level of expression in human skin is associated with psoriasis and squamous cell carcinomas. Finally, we provide evidence that inhibition of miR-21-3p reduces UV-induced cutaneous inflammation in ex vivo human skin biopsies, thereby underlining the clinical relevance of miRNA-based topical therapies for cutaneous disorders.

History of the Tfam gene in primates.

Tfam is a single copy nuclear gene mapping on chromosome 10 in human and mouse, 20 in rat and 12 in Presbytis cristata. It encodes for an HMG (high-mobility-group) protein showing a high affinity with the two transcriptional promoters and other mitochondrial DNA regions. It is an activator of mitochondrial transcription acting in the presence of mitochondrial RNA polymerase and of transcription factor B. Other interesting features of Tfam gene in human and rat are reported such as the existence of a smaller isoform, originated by an alternative splicing mechanism of the exon 5 (delta5 isoform) and the presence of different processed pseudogenes in addition to the active copy of the gene. In order to widen knowledge about Tfam gene and the appearance of some of its properties in the evolutionary history of primates, we have studied some aspects of this gene in different species. In particular we have determined its chromosomal localization, suggesting that its locus is highly conserved; we have searched for the presence of the delta5 isoform, demonstrating that it is present only in hominids; we have provided evidence of Tfam processed pseudogenes in the majority of the analysed genomes. Sequence data from this article have been deposited in the EMBL nucleotide database.

Characterization of the mtTFA gene and identification of a processed pseudogene in rat.

Mitochondrial DNA replication and transcription are regulated from essential nucleus-encoded components that interact with the mitochondrial (mt) D-loop region. Among these there is the mitochondrial transcription factor A (mtTFA or Tfam). We have determined the sequence of the cDNA mtTFA in rat and have demonstrated that the gene has a mosaic organization with six introns whose sizes we have calculated. A differential splicing transcript lacking exon 5 has been detected in all assayed tissues and represents 9.85% of the full length transcript. Beside the gene which is homologous to the one found in man and mouse, rat nuclear genome contains at least 12 copies of this gene or genome fragments with high similarity to mtTFA. We have determined the sequence of one of these copies. This resulted to have 76.26% similarity to the active gene but to lack introns, suggesting it might be a processed pseudogene. RT-PCR experiments have demonstrated that this pseudogene (psi mtTFA) is transcribed in liver tissue.

Molecular strategies in Metazoan genomic evolution.

During the evolution of Metazoa, the mitochondrial genome has remained practically unchanged as indicated by its small size and constant gene content in each lineage, although several evolutionary processes have taken place. In contrast, the nuclear genome of Metazoa has undergone dramatic changes, as is demonstrated by some entire genomes completely sequenced so far. The expansion of gene families and the appearance of new functions and new regulatory circuits are among the most prominent features. Here, we report a description of the evolution of the p53 gene family as an example of expansion of both genetic complexity and gene expression of the nuclear genome.

Bax is necessary for PGC1α pro-apoptotic effect in colorectal cancer cells.

We have recently shown that the transcriptional coactivator PGC1α, a master regulator of mitochondrial biogenesis and function, is involved in the control of the intestinal epithelium cell fate. Furthermore, PGC1α protects against colon cancer formation by promoting ROS accumulation and, consequently, mitochondria-mediated apoptosis. Here we provide an additional mechanistic insight into the tumor suppressor activity of PGC1α showing that its pro-apoptotic effect is mediated by Bax. In fact, PGC1α overexpression in HCT116 Bax (-/-) colorectal cancer cells stimulates mitochondrial production and activity, but it fails to induce cell death as well as to oppose tumor growth in the xenograft model. The lack of ROS accumulation in the Bax (-/-) cells strengthens our view that the PGC1α-induced oxidative burst represents one of the main apoptosis-driving factors in colorectal cancer cells.

Intestinal specific LXR activation stimulates reverse cholesterol transport and protects from atherosclerosis.

Several steps of the HDL-mediated reverse cholesterol transport (RCT) are transcriptionally regulated by the nuclear receptors LXRs in the macrophages, liver, and intestine. Systemic LXR activation via synthetic ligands induces RCT but also causes increased hepatic fatty acid synthesis and steatosis, limiting the potential therapeutic use of LXR agonists. During the last few years, the participation of the intestine in the control of RCT has appeared more evident. Here we show that while hepatic-specific LXR activation does not contribute to RCT, intestinal-specific LXR activation leads to decreased intestinal cholesterol absorption, improved lipoprotein profile, and increased RCT in vivo in the absence of hepatic steatosis. These events protect against atherosclerosis in the background of the LDLR-deficient mice. Our study fully characterizes the molecular and metabolic scenario that elects the intestine as a key player in the LXR-driven protective environment against cardiovascular disease.

Pseudogenes in metazoa: origin and features.

The complete genome sequences with their annotations are a considerable resource in biology, particularly in understanding the global structure of the genetic material at the molecular level. The reason why some eukaryotic genomes contain large quantities of apparently unnecessary DNA, namely pseudogenes, while others seem to invest in more efficient thinning processes or are equipped with protection systems against parasitic elements still remains a mystery. Several genome-wide surveys have been undertaken to identify pseudogenes in the completely sequenced genome, bringing to light some differences both in their amount and distribution. Since pseudogenes are important resources in evolutionary and comparative genomics - as 'molecular fossils' - in this paper, a survey on the origins, features, abundance and localisation of the different pseudogenes is reported. As an example of genes producing processed pseudogenes, some experimental data obtained in the authors' laboratories from the study of a nuclear gene coding for the mitochondrial transcription factor A (mtTFA), a key regulator of mitochondrial biogenesis, are also reported.