In addition to acetylation, eight types of structurally and functionally different short-chain acylations have recently been identified as important histone Lys modifications: propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation, glutarylation, crotonylation and β-hydroxybutyrylation. These modifications are regulated by enzymatic and metabolic mechanisms and have physiological functions, which include signal-dependent gene activation and metabolic stress.
The Lasker Awards
The Lasker Awards program was created in 1945 by Albert and Mary Lasker to shine a spotlight on fundamental biological discoveries and clinical advances that improve human health, and to draw attention to the importance of public support of science. The Lasker Awards recognize the contributions of researchers, clinician scientists, and public servants who have made major advances in the understanding, diagnosis, treatment, cure, or prevention of disease. We would like to congratulate the winners!
Lasker Basic Medical Research Award
Michael Grunstein, Ph.D.
Professor, Department of Biological Chemistry, David Geffen School of Medicine at UCLA
Michael Grunstein has been jointly awarded the Lasker Basic Medical Research Award along with C. David Allis. He laid the groundwork for understanding the role of nucleosomes and their modifiable tails in gene expression.
C. David Allis, Ph.D.
Professor, Laboratory of Chromatin Biology, The Rockefeller University
David Allis has been jointly awarded the Lasker Basic Medical Research Award along with Michael Grunstein. He furthered understanding of the role of nucleosomes in the regulation of gene expression by identifying enzymes that are crucial in modifying nucleosomes and hence have a role in switching genes on and off.
Lasker~DeBakey Clinical Medical Research Award
John (Iain) B. Glen, Ph.D.
Former Anesthesiology Team Leader and Clinical Specialist in Anesthesia,AstraZeneca
Iain Glen has been awarded the Lasker~DeBakey Clinical Medical Research Award for discovery and development of induction of the anesthesia agent propofol. Glen’s perseverance in its development has resulted in the delivery of a versatile anaesthetic for which there are minimal residual effects to many individuals, enabling countless surgeries and screening procedures.
Lasker~Koshland Special Achievement Award in Medical Science
Joan Argetsinger Steitz, Ph.D.
Professor of Molecular Biophysics and Biochemistry, Yale University, Howard Hughes Medical Institute
Joan Argetsinger Steitz has been presented the Special Achievement Award in Medical Science for her contributions as a pioneering RNA biologist, mentor and role model. She has contributed to understanding of RNA processing and been a champion of both rising scientists and women in science.
Lasker Basic Medical Research Award
Over the past few decades, epigenetics has evolved from a collection of curious biological phenomena to a functionally dissected research field. In this article, the authors provide a personal perspective on the advances of research into epigenetics — from its historical origins to its modern era — with a focus on molecular breakthroughs.
Four papers in this issue tackle the hot topic of chromatin remodelling, specifically, how methyl marks on chromatin are 'read' by the proteins that interact with them. Two report on BPTF (bromodomain and PHD domain transcription factor), a subunit of NURF, the nucleosome remodelling factor. It contains a domain known as a PHD finger, which is shown to bind to histone H3 trimethylated at lysine 4 (H3K4) and to maintain proper activity at developmentally critical HOX genes. The accompanying structural study of the complex explains how the site specificity for H3K4 is achieved. The two other papers reveal that the PHD domain of tumour suppressor ING2 also recognizes trimethylated H3K4, and link the histone mark to repression of transcription. The four papers together establish certain PHD finger domains as previously unrecognized chromatin-binding modules. In a News and Views piece, Peter B. Becker discusses what these papers tell us about the function of the chemical modifications of histone tails.
It is important for eukaryotic cells to repair DNA double-strand breaks, as failure to do so can cause genomic instability, carcinogenesis and cell death. An early cellular response to DNA double-strand breaks in mammals is the phosphorylation of the specialized histone H2A.X at serine 139. A further, previously unknown H2A.X phosphorylation site has now been identified at tyrosine 142. Phosphorylation at this site is catalysed by the chromatin remodelling factor WSTF, which is frequently absent in patients with Williams–Beuren syndrome, a developmental disease caused by a deletion on human chromosome 7. This work calls attention to a novel pathway specifically regulating chromatin reorganization during the mammalian cell DNA damage response, and sheds light on the molecular basis of Williams–Beuren syndrome.
Histone post-translational modifications have crucial roles in genome management, in part by recruiting specific factors that alter the structural properties of chromatin. These so-called effector complexes often comprise multiple histone-binding modules that may act in concert to regulate chromatin structure and DNA-related activities.
A chromosomal translocation found in certain acute myeloid leukaemia (AML) patients results in fusion of the PHD finger of a chromatin-binding protein to a nucleoporin NUP98. One such fusion protein is now reported to be a potent oncoprotein inducing AML. Introducing mutations in the PHD finger that abrogate its binding to histone H3 trimethylated at Lys4 is shown to abolish tumorigenesis. By binding chromatin, the NUP98-PHD fusion seems to lock developmentally important genes into an active state. Deregulation of an 'effector' of histone modifications can therefore lead to oncogenesis.
Every amino acid matters: essential contributions of histone variants to mammalian development and disease
Increasing evidence suggests crucial functions for histone variants in diverse biological processes. This Review examines the roles of histone variants in mammalian germ cell and embryonic development, as well as the consequences of their aberrant regulation in human disease.
Finley et al. show that Brd4 is dispensable for self-renewal and pluripotency in murine embryonic stem cells (ESCs). In metastable ESCs, Brd4 independence can be achieved by increasing the expression of the pluripotency transcription factors Oct4, Sox2 and Nanog as long as Tet1/2 are present.
The recent mapping of histone modifications across theSaccharomyces cerevisiaegenome has allowed the analysis of how combinations of modified and unmodified chromatin states relate to each other and particularly to chromosomal landmarks, such as heterochromatin, centromeres, promoters and coding regions.
Koshland Special Achievement Award in Medical Science
The X-ray crystal structure and biochemical analysis of a triple helix formed between the expression and nuclear retention element (ENE) and the 3′ poly(A) tail of the human long noncoding RNA MALAT-1 reveals the basis of its stability and how it confers resistance to degradation.