Chromatin, the physiological template of all eukaryotic genetic information, is subject to a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA. Distinct histone amino-terminal modifications can generate synergistic or antagonistic interaction affinities for chromatin-associated proteins, which in turn dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states. The combinatorial nature of histone amino-terminal modifications thus reveals a “histone code” that considerably extends the information potential of the genetic code. We propose that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.

/pdf/translating-the-histone-code-l291mddcr9.pdf

Translating the Histone Code

Chromatin is not an inert structure, but rather an instructive DNA scaffold that can respond to external cues to regulate the many uses of DNA. A principle component of chromatin that plays a key role in this regulation is the modification of histones. There is an ever-growing list of these modifications and the complexity of their action is only just beginning to be understood. However, it is clear that histone modifications play fundamental roles in most biological processes that are involved in the manipulation and expression of DNA. Here, we describe the known histone modifications, define where they are found genomically and discuss some of their functional consequences, concentrating mostly on transcription where the majority of characterisation has taken place.

/pdf/regulation-of-chromatin-by-histone-modifications-35b8poynlc.pdf

Regulation of chromatin by histone modifications

Objectives: Lao Juan (LJ, 劳倦) is a syndrome described in Chinese medicine (CM) that manifests with : Lao Juan (LJ, 劳倦) is a syndrome described in Chinese medicine (CM) that manifests with fatigue, fever, spontaneous sweating, indigestion, work-induced pain, weakness of the limbs, and shortness of breath. fatigue, fever, spontaneous sweating, indigestion, work-induced pain, weakness of the limbs, and shortness of breath. The present study was conducted to examine the reliability and validity of a Lao Juan Questionnaire (LJQ). The present study was conducted to examine the reliability and validity of a Lao Juan Questionnaire (LJQ). Methods: A total of 151 outpatients and 73 normal subjects were asked to complete the LJQ. Seventy-three normal subjects A total of 151 outpatients and 73 normal subjects were asked to complete the LJQ. Seventy-three normal subjects were additionally asked to complete the Chalder Fatigue Scale (CFS). Twelve clinicians determined whether the were additionally asked to complete the Chalder Fatigue Scale (CFS). Twelve clinicians determined whether the 151 outpatients exhibited LJ or not. The internal consistency and construct validity for the LJQ were estimated using 151 outpatients exhibited LJ or not. The internal consistency and construct validity for the LJQ were estimated using data from the outpatient subjects. The CFS data were used to examine the concurrent validity of the LJQ. Total LJQ data from the outpatient subjects. The CFS data were used to examine the concurrent validity of the LJQ. Total LJQ scores and the clinicians' diagnoses of the outpatients were used to perform receiver operating characteristics (ROC) scores and the clinicians' diagnoses of the outpatients were used to perform receiver operating characteristics (ROC) curve analyses and to defi ne an optimum cut-off score for the LJQ. curve analyses and to defi ne an optimum cut-off score for the LJQ. Results: The 19-item LJQ had satisfactory internal : The 19-item LJQ had satisfactory internal consistency (α=0.828) and concurrent validity, with signifi cant correlations between the LJQ and the CFS subscales. consistency (α=0.828) and concurrent validity, with signifi cant correlations between the LJQ and the CFS subscales. In the test of construct validity using principal component analysis, a total of six factors were extracted, and the overall In the test of construct validity using principal component analysis, a total of six factors were extracted, and the overall variance explained by all factors was 59.5%. In ROC curve analyses, the sensitivity, specifi city, and area under the variance explained by all factors was 59.5%. In ROC curve analyses, the sensitivity, specifi city, and area under the curve were 76.0%, 59.2%, and 0.709, respectively. The optimum cut-off score was defi ned as six points. curve were 76.0%, 59.2%, and 0.709, respectively. The optimum cut-off score was defi ned as six points. Conclusions: Our results suggest that the LJQ is a reliable and valid instrument for evaluating LJ. Our results suggest that the LJQ is a reliable and valid instrument for evaluating LJ. KEYWORDS Chinese medicine, chronic fatigue syndrome, Chinese medicine-pattern Chinese medicine, chronic fatigue syndrome, Chinese medicine-pattern

Development and Validation of A

Polycomb group (PcG) proteins play important roles in maintaining the silent state of HOX genes. Recent studies have implicated histone methylation in long-term gene silencing. However, a connection between PcG-mediated gene silencing and histone methylation has not been established. Here we report the purification and characterization of an EED-EZH2 complex, the human counterpart of the Drosophila ESC-E(Z) complex. We demonstrate that the complex specifically methylates nucleosomal histone H3 at lysine 27 (H3-K27). Using chromatin immunoprecipitation assays, we show that H3-K27 methylation colocalizes with, and is dependent on, E(Z) binding at an Ultrabithorax (Ubx) Polycomb response element (PRE), and that this methylation correlates with Ubx repression. Methylation on H3-K27 facilitates binding of Polycomb (PC), a component of the PRC1 complex, to histone H3 amino-terminal tail. Thus, these studies establish a link between histone methylation and PcG-mediated gene silencing.

https://science.sciencemag.org/content/sci/298/5595/1039.full.pdf

Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing

https://www.chem.uwec.edu/Chem412_S05/Pages/presentations/giesemc/Shi_et_al_2004.pdf

Histone demethylation mediated by the nuclear amine oxidase homolog lsd1

Epigenetics describes changes in genome function that occur without a change in the DNA sequence. Dosage compensation is a prime example of the regulation of gene expression by an epigenetic mechanism. Dosage compensation has evolved to balance the expression of sex-linked genes in males and females, which possess different numbers of sex chromosomes. However, the genetic sequence of the chromosomes is the same in both sexes. This mechanism therefore needs (1) to function in a sex-specific manner, (2) to target the sex chromosome from amongst the autosomes and (3) to establish and maintain through development a precise, equalised level of gene expression in one sex compared to the other. The process by which dosage compensation is orchestrated has been well characterised in fruit flies and mammals. Although each has evolved a specific dosage-compensation mechanism, these systems share some underlying themes; the molecular components that mediate dosage compensation in both include non-coding RNA molecules, which act as nucleation points for the compensation process. Both systems utilise chromatin-modifying enzymes to remodel large domains of a chromosome. This review will discuss the mechanism of dosage compensation in Drosophila in light of recent developments that have brought into question the previous model of dosage compensation.

MSL proteins and the regulation of gene expression.

The stability of the genome is constantly under attack from both endogenous and exogenous DNA damaging agents. These agents, as well as naturally occurring processes such as DNA replication and recombination can result in DNA double-strand breaks (DSBs). DSBs are potentially lethal and so eukaryotic cells have evolved an elaborate pathway, the DNA damage response, which detects the damage, recruits proteins to the DSBs, activates checkpoints to stall cell cycle progression and ultimately mediates repair of the damaged DNA. As the DSBs occur in the context of chromatin, execution of this response is partly orchestrated through the modification of the DNA-bound histone proteins. These histone modifications include the addition or removal of various chemical groups or small peptides and function to change the chromatin structure or to attract factors involved in the DNA damage response, and as such, are particularly important in the early stages of the DNA damage response. This review will focus on such modifications, the enzymes responsible and also highlights their importance by reporting known roles for these modifications in genome stability and disease.

Core and linker histone modifications involved in the DNA damage response.

hMSL2 (male-specific lethal 2, human) is a RING finger protein with ubiquitin ligase activity. Although it has been shown to target histone H2B at lysine 34 and p53 at lysine 351, suggesting roles in transcription regulation and apoptosis, its function in these and other processes remains poorly defined. To further characterize this protein, we have disrupted the Msl2 gene in chicken DT40 cells. Msl2−/− cells are viable, with minor growth defects. Biochemical analysis of the chromatin in these cells revealed aberrations in the levels of several histone modifications involved in DNA damage response pathways. DNA repair assays show that both Msl2−/− chicken cells and hMSL2-depleted human cells have defects in non-homologous end joining (NHEJ) repair. DNA damage assays also demonstrate that both Msl2 and hMSL2 proteins are modified and stabilized shortly after induction of DNA damage. Moreover, hMSL2 mediates modification, presumably ubiquitylation, of a key DNA repair mediator 53BP1 at lysine 1690. Similarly, hMSL1 and hMOF (males absent on the first) are modified in the presence of hMSL2 shortly after DNA damage. These data identify a novel role for Msl2/hMSL2 in the cellular response to DNA damage. The kinetics of its stabilization suggests a function early in the NHEJ repair pathway. Moreover, Msl2 plays a role in maintaining normal histone modification profiles, which may also contribute to the DNA damage response.

/pdf/msl2-is-a-novel-component-of-the-vertebrate-dna-damage-44brrh373f.pdf

Stephen Rea

Papers

MSL proteins and the regulation of gene expression.

Core and linker histone modifications involved in the DNA damage response.

Msl2 is a novel component of the vertebrate DNA damage response.