Nucleoside diphosphate kinases 1 and 2 regulate a protective liver response to a high-fat diet.

The synthesis of fatty acids from acetyl-coenzyme A (AcCoA) is deregulated in diverse pathologies, including cancer. Here, we report that fatty acid accumulation is negatively regulated by nucleoside diphosphate kinases 1 and 2 (NME1/2), housekeeping enzymes involved in nucleotide homeostasis that were recently found to bind CoA. We show that NME1 additionally binds AcCoA and that ligand recognition involves a unique binding mode dependent on the CoA/AcCoA 3' phosphate.

ATAD2 controls chromatin-bound HIRA turnover.

Taking advantage of the evolutionary conserved nature of ATAD2, we report here a series of parallel functional studies in human, mouse, and to investigate ATAD2's conserved functions. In , the deletion of ortholog, , leads to a dramatic decrease in cell growth, with the appearance of suppressor clones recovering normal growth. The identification of the corresponding suppressor mutations revealed a strong genetic interaction between Abo1 and the histone chaperone HIRA.

Histone Variant H2A.L.2 Guides Transition Protein-Dependent Protamine Assembly in Male Germ Cells.

Histone replacement by transition proteins (TPs) and protamines (Prms) constitutes an essential step for the successful production of functional male gametes, yet nothing is known on the underlying functional interplay between histones, TPs, and Prms. Here, by studying spermatogenesis in the absence of a spermatid-specific histone variant, H2A.L.

Genome-wide nucleosome specificity and function of chromatin remodellers in ES cells.

ATP-dependent chromatin remodellers allow access to DNA for transcription factors and the general transcription machinery, but whether mammalian chromatin remodellers target specific nucleosomes to regulate transcription is unclear. Here we present genome-wide remodeller-nucleosome interaction profiles for the chromatin remodellers Chd1, Chd2, Chd4, Chd6, Chd8, Chd9, Brg1 and Ep400 in mouse embryonic stem (ES) cells. These remodellers bind one or both full nucleosomes that flank micrococcal nuclease (MNase)-defined nucleosome-free promoter regions (NFRs), where they separate divergent transcription.

Atad2 is a generalist facilitator of chromatin dynamics in embryonic stem cells.

Although the conserved AAA ATPase and bromodomain factor, ATAD2, has been described as a transcriptional co-activator upregulated in many cancers, its function remains poorly understood. Here, using a combination of ChIP-seq, ChIP-proteomics, and RNA-seq experiments in embryonic stem cells where Atad2 is normally highly expressed, we found that Atad2 is an abundant nucleosome-bound protein present on active genes, associated with chromatin remodelling, DNA replication, and DNA repair factors. A structural analysis of its bromodomain and subsequent investigations demonstrate that histone acetylation guides ATAD2 to chromatin, resulting in an overall increase of chromatin accessibility and histone dynamics, which is required for the proper activity of the highly expressed gene fraction of the genome.

Lessons from yeast on emerging roles of the ATAD2 protein family in gene regulation and genome organization.

ATAD2, a remarkably conserved, yet poorly characterized factor is found upregulated and associated with poor prognosis in a variety of independent cancers in human. Studies conducted on the yeast Saccharomyces cerevisiae ATAD2 homologue, Yta7, are now indicating that the members of this family may primarily be regulators of chromatin dynamics and that their action on gene expression could only be one facet of their general activity. In this review, we present an overview of the literature on Yta7 and discuss the possibility of translating these findings into other organisms to further define the involvement of ATAD2 and other members of its family in regulating chromatin structure and function both in normal and pathological situations.

Chromatin-to-nucleoprotamine transition is controlled by the histone H2B variant TH2B.

The conversion of male germ cell chromatin to a nucleoprotamine structure is fundamental to the life cycle, yet the underlying molecular details remain obscure. Here we show that an essential step is the genome-wide incorporation of TH2B, a histone H2B variant of hitherto unknown function. Using mouse models in which TH2B is depleted or C-terminally modified, we show that TH2B directs the final transformation of dissociating nucleosomes into protamine-packed structures.

Malignant genome reprogramming by ATAD2.

Background: Unscheduled expression of critical cellular regulators could be central to malignant genome reprogramming and tumor establishment. One such factor appears to be ATAD2, a remarkably conserved protein normally predominantly expressed in germ cells but almost systematically over-expressed in a variety of unrelated cancers. The presence of a bromodomain adjacent to an AAA type ATPase domain, points to ATAD2 as a factor preliminarily acting on chromatin structure and function.

Bromodomain-dependent stage-specific male genome programming by Brdt.

Male germ cell differentiation is a highly regulated multistep process initiated by the commitment of progenitor cells into meiosis and characterized by major chromatin reorganizations in haploid spermatids. We report here that a single member of the double bromodomain BET factors, Brdt, is a master regulator of both meiotic divisions and post-meiotic genome repackaging. Upon its activation at the onset of meiosis, Brdt drives and determines the developmental timing of a testis-specific gene expression program.

Genomic binding of Pol III transcription machinery and relationship with TFIIS transcription factor distribution in mouse embryonic stem cells.

RNA polymerase (Pol) III synthesizes the tRNAs, the 5S ribosomal RNA and a small number of untranslated RNAs. In vitro, it also transcribes short interspersed nuclear elements (SINEs). We investigated the distribution of Pol III and its associated transcription factors on the genome of mouse embryonic stem cells using a highly specific tandem ChIP-Seq method.

Molecular models for post-meiotic male genome reprogramming.

The molecular basis of post-meiotic male genome reorganization and compaction constitutes one of the last black boxes in modern biology. Although the successive transitions in DNA packaging have been well described, the molecular factors driving these near genome-wide reorganizations remain obscure. We have used a combination of different approaches aiming at the discovery of critical factors capable of directing the post-meiotic male genome reprogramming, which is now shedding new light on the nature of the fundamental mechanisms controlling post-meiotic histone replacement and genome compaction.

From meiosis to postmeiotic events: the secrets of histone disappearance.

One of the most obscure phenomena in modern biology is the near genome-wide displacement of histones that occurs during the postmeiotic phases of spermatogenesis in many species. Here we review the literature to show that, during spermatogenic differentiation, three major molecular mechanisms come together to 'prepare' the nucleosomes for facilitated disassembly and histone removal.

Histone acetyltransferase CBP is vital to demarcate conventional and innate CD8+ T-cell development.

Defining the chromatin modifications and transcriptional mechanisms that direct the development of different T-cell lineages is a major challenge in immunology. The transcriptional coactivators CREB binding protein (CBP) and the closely related p300, which comprise the KAT3 family of histone/protein lysine acetyltransferases, interact with over 50 T-lymphocyte-essential transcriptional regulators. We show here that CBP, but not p300, modulates the thymic development of conventional adaptive T cells versus those having unconventional innate functions.

A new insight into male genome reprogramming by histone variants and histone code.

The very nature of the packed male genome, essentially containing non-histone proteins, suggests that most of the epigenetic marks which have been defined in somatic cells are not valid in mature male gametes and that new specific rules prevail for the transmission of epigenetic information in male germ cells. Recent investigations are now uncovering a male-specific genome reprogramming mechanism, which likely cooperates with and extends beyond DNA methylation, specifying different regions of the genome and which could encode a new type of epigenetic information transmitted to the egg. Here we highlight the general traits of this unconventional male-specific epigenetic code, which largely relies on the use of histone variants and specific histone modifications.

Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development.

The global transcriptional coactivators CREB-binding protein (CBP) and the closely related p300 interact with over 312 proteins, making them among the most heavily connected hubs in the known mammalian protein-protein interactome. It is largely uncertain, however, if these interactions are important in specific cell lineages of adult animals, as homozygous null mutations in either CBP or p300 result in early embryonic lethality in mice. Here we describe a Cre/LoxP conditional p300 null allele (p300flox) that allows for the temporal and tissue-specific inactivation of p300.

Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression.

The C-terminal activation domain (C-TAD) of the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha binds the CH1 domains of the related transcriptional coactivators CREB-binding protein (CBP) and p300, an oxygen-regulated interaction thought to be highly essential for hypoxia-responsive transcription. The role of the CH1 domain in vivo is unknown, however. We created mutant mice bearing deletions in the CH1 domains (DeltaCH1) of CBP and p300 that abrogate their interactions with the C-TAD, revealing that the CH1 domains of CBP and p300 are genetically non-redundant and indispensable for C-TAD transactivation function.

The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism.

Glucose homeostasis is regulated systemically by hormones such as insulin and glucagon, and at the cellular level by energy status. Glucagon enhances glucose output from the liver during fasting by stimulating the transcription of gluconeogenic genes via the cyclic AMP-inducible factor CREB (CRE binding protein). When cellular ATP levels are low, however, the energy-sensing kinase AMPK inhibits hepatic gluconeogenesis through an unknown mechanism.

Lactate and energy metabolism in male germ cells.

Various alterations in germ cell proliferation/differentiation, survival and energy metabolism are potentially involved in hypospermatogenesis leading to male infertility. Several reviews have been devoted to the different processes whose alteration might underlie hypospermatogenesis, except for energy metabolism in the testis. Energy metabolism in the testis exhibits some specificity in that lactate is the central energy metabolite used by germ cells.

Loss of CBP causes T cell lymphomagenesis in synergy with p27Kip1 insufficiency.

CBP can function as a tumor suppressor, but the mechanisms that govern oncogenesis in its absence are unknown. Here we show that CBP inactivation in mouse thymocytes leads to lymphoma. Although CBP has been implicated in the transactivation functions of p53, development of these tumors does not seem to involve loss of p53 activity.

Developmental and hormonal regulation of the monocarboxylate transporter 2 (MCT2) expression in the mouse germ cells.

During spermatogenesis, postmeiotic germ cells utilize lactate produced by Sertoli cells as an energy metabolite. While the hormonal regulation of lactate production in Sertoli cells has been relatively well established, the transport of this energy substrate to the germ cells, particularly via the monocarboxylate transporters (MCTs), as well as the potential endocrine control of such a process remain to be characterized. Here, we report the developmentally and hormonally regulated expression of MCT2 in the testis.

A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis.

The coactivators CBP (Cre-element binding protein (CREB)-binding protein) and its paralogue p300 are thought to supply adaptor molecule and protein acetyltransferase functions to many transcription factors that regulate gene expression. Normal development requires CBP and p300, and mutations in these genes are found in haematopoietic and epithelial tumours. It is unclear, however, which functions of CBP and p300 are essential in vivo.