We present an analysis of over 1,100 of the approximately 10,000 predicted proteins encoded by the genome sequence of the filamentous fungus Neurospora crassa. Seven major areas of Neurospora genomics and biology are covered. First, the basic features of the genome, including the automated assembly, gene calls, and global gene analyses are summarized. The second section covers components of the centromere and kinetochore complexes, chromatin assembly and modification, and transcription and translation initiation factors. The third area discusses genome defense mechanisms, including repeat induced point mutation, quelling and meiotic silencing, and DNA repair and recombination. In the fourth section, topics relevant to metabolism and transport include extracellular digestion; membrane transporters; aspects of carbon, sulfur, nitrogen, and lipid metabolism; the mitochondrion and energy metabolism; the proteasome; and protein glycosylation, secretion, and endocytosis. Environmental sensing is the focus of the fifth section with a treatment of two-component systems; GTP-binding proteins; mitogen-activated protein, p21-activated, and germinal center kinases; calcium signaling; protein phosphatases; photobiology; circadian rhythms; and heat shock and stress responses. The sixth area of analysis is growth and development; it encompasses cell wall synthesis, proteins important for hyphal polarity, cytoskeletal components, the cyclin/cyclin-dependent kinase machinery, macroconidiation, meiosis, and the sexual cycle. The seventh section covers topics relevant to animal and plant pathogenesis and human disease. The results demonstrate that a large proportion of Neurospora genes do not have homologues in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe. The group of unshared genes includes potential new targets for antifungals as well as loci implicated in human and plant physiology and disease.

/pdf/lessons-from-the-genome-sequence-of-neurospora-crassa-1vsx4nukvq.pdf

Lessons from the Genome Sequence of Neurospora crassa: Tracing the Path from Genomic Blueprint to Multicellular Organism

The differentiation from multipotent hematopoietic stem cells (HSC) to mature and functional blood cells requires the finely tuned regulation of gene expression at each stage of development. Specific transcription factors play a key role in this process as they modulate the expression of their target genes in an exquisitely lineage-specific manner. A large number of important transcriptional regulators have been identified which establish and maintain specific gene expression patterns during hematopoietic development. Hematopoiesis is therefore a paradigm for investigating how transcription factors function in mammalian cells, thanks also to the evolution of genome-wide and the next-generation sequencing technologies. In this review, we focus on the current knowledge of the biological and functional properties of the hematopoietic master regulator RUNX1 (also known as AML1, CBFA2, PEBP2aB) transcription factor and its main downstream target PU.1. We will outline their relationship in determining the fate of the myeloid lineage during normal stem cell development and under conditions when hematopoietic development is subverted by leukemic transformation.

/pdf/the-runx1-pu-1-axis-in-the-control-of-hematopoiesis-4yq08o3tmm.pdf

The RUNX1–PU.1 axis in the control of hematopoiesis

Myeloid Differentiation (MyD) primary response and Growth Arrest DNA-Damage (Gadd) genes comprise a set of overlapping genes, including known (IRF-1, EGR-1, Jun) and novel (MyD88, Gadd45alpha MyD118/Gadd45beta, GADD45gamma, MyD116/Gadd34) genes, that have been cloned by virtue of there being co-ordinately induced upon the onset of terminal myeloid differentiation. This review delineates the role MyD genes play in blood cell development, where they function as positive regulators of terminal differentiation, lineage specific blood cell development and control of blood cell homeostasis, including growth inhibition and apoptosis.

Myeloid differentiation (MyD) primary response genes in hematopoiesis.

Genotoxic stresses activate intracellular signaling molecules, which lead to growth arrest, DNA repair, and/or apoptosis. Among these molecules are the growth arrest and DNA damage protein 34 (GADD34) and the Src-related protein tyrosine kinase Lyn. Here, we report that these two proteins physically and functionally interact to regulate DNA damage-induced apoptosis. Multiple isolates of GADD34 and the related murine protein MyD116 were identified as binding partners of Lyn in a yeast two-hybrid screen. The specific interaction was confirmed by in vitro association of GADD34 with glutathione S-transferase fusion proteins containing the Src Homology 3 (SH3) domain of Lyn, as well as coimmunoprecipitation of GADD34 and Lyn from mammalian cells. GADD34 was tyrosine-phosphorylated in vivo in a Lyn-dependent manner. Lyn efficiently phosphorylated affinity-purified GADD34 in vitro. Lyn negatively regulated the proapoptotic function of GADD34 in a kinase-dependent manner. Expression of wild-type, but not kinase-inactive, Lyn weakened promotion of apoptosis by GADD34 following treatment with methyl-methanesulfonate or ionizing radiation in HEK293 and HeLa cells. In contrast, pretreatment of cells with the Src-specific tyrosine kinase inhibitor PP1 strengthened promotion of apoptosis by GADD34. We propose that Lyn regulates the proapoptotic function of GADD34 by binding and phosphorylating it.

https://www.pnas.org/content/pnas/98/18/10172.full.pdf

Interaction between growth arrest-DNA damage protein 34 and Src kinase Lyn negatively regulates genotoxic apoptosis

The Human SNF5/INI1 Protein Facilitates the Function of the Growth Arrest and DNA Damage-inducible Protein (GADD34) and Modulates GADD34-bound Protein Phosphatase-1 Activity

Ig-like transcripts (ILT/leukocyte Ig-like receptor/monocyte/macrophage Ig-like receptor or CD85) are encoded on human chromosome 19q13.4, designated the human leukocyte receptor complex, and are predominantly expressed on myeloid lineage cells. We investigated the transcriptional regulation of ILT1, ILT2, and ILT4 genes to elucidate control mechanisms operating on the specific expression of ILT receptors. Inhibitory ILT2 and ILT4 both have a similar genomic structure, in which the ∼160-bp 5′-flanking regions function as core promoters with critically important PU.1 binding sites. However, an Sp1 family-binding GC-box is more influential in trans -activation of ILT2 than ILT4. Additionally, ILT4 transcription is tightly regulated by chromatin modifications accompanied by histone acetylation, which strictly controls expression within myeloid lineage cells. Activating ILT1 carries a core promoter corresponding to the intronic region of ILT2 and ILT4, where PU.1 and Runx1 binding sites are essential, but a downstream heat shock element also augments promoter activity. Thus, each ILT is regulated by a distinct transcriptional mechanism, although PU.1 acts as a common trans -acting factor. We also found that human CMV infection strongly trans -activates inhibitory ILT2 and ILT4 genes through the expression of immediate-early proteins.

/pdf/transcriptional-regulation-of-ilt-family-receptors-1pfjtmssyx.pdf

Transcriptional Regulation of ILT Family Receptors

GADD34 is one of a subset of proteins induced after DNA damage or cell growth arrest. To examine the function of GADD34, we used the yeast two-hybrid system to clone the protein that interacts with murine GADD34. As bait we used the product of the partial GADD34 cDNA, including the regions rich in proline, glutamic acid, serine and threonine (PEST) and gamma(1)34.5 regions. A cDNA clone, named GAHSP40, which is a mouse DnaJ family protein with a high similarity to human HLJ1 was cloned. The interaction between GADD34 and GAHSP40 in cultured cells was confirmed by a co-immunoprecipitation experiment and in NIH 3T3 cells by two-hybrid analysis in vivo. For binding of the two proteins, the gamma(1)34.5-similar region of GADD34 was necessary; however, the PEST region was also involved and the C-terminus of GAHSP40, but not the J-domain, was important. GAHSP40 was detected in all mouse tissues examined, but a different transcript was found in the testis. Both GADD34 mRNA and GAHSP40 mRNA were significantly elevated by treatment with methyl methanesulphonate, although the time courses were different. In addition, both GAHSP40 and GADD34 mRNA were induced by heat shock.

/pdf/interaction-between-dna-damage-protein-gadd34-and-a-new-2iivkvo7hv.pdf

Interaction Between DNA-damage Protein GADD34 and a New Member of the Hsp40 Family of Heat Shock Proteins That Is Induced by a DNA-damaging Reagent

The new heat shock protein (GAHSP40), which binds to Gadd34, is a member of the Hsp40 family gene and has a J domain, which is similar to bacterial DNAJ. We have isolated and sequenced the mouse GAHSP40 gene including 1.6 kb of the 5′-flanking region. Primer extension analysis revealed that the transcription initiation site was located 36-bp upstream of the ATG translation initiation codon. In order to identify the heat-responsive regions in the GAHSP40, NIH3T3 cells were transiently transfected with a series of 5′ terminus-truncated mutants of the GAHSP40 promoter linked to the luciferase reporter gene. We found that the region of −284 to −184 bp from initiation start site responded to heat shock treatment. By the gel shift analysis, we found the heat shock elements (HSEs) located in this region from −257 to −225. This HSEs has five 5 bp motifs. The transfection studies using HSEs mutant vectors revealed that those 3′ two 5 bp motifs are essential for heat responsive transcription. J. Cell. Biochem. 84: 401–407, 2002. © 2001 Wiley-Liss, Inc.

Genomic cloning and promoter analysis of the GAHSP40 gene

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Transcriptional Regulation of ILT Family Receptors

Interaction Between DNA-damage Protein GADD34 and a New Member of the Hsp40 Family of Heat Shock Proteins That Is Induced by a DNA-damaging Reagent

Genomic cloning and promoter analysis of the GAHSP40 gene