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1.
Nature ; 589(7841): 293-298, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33299182

RESUMEN

H1 linker histones are the most abundant chromatin-binding proteins1. In vitro studies indicate that their association with chromatin determines nucleosome spacing and enables arrays of nucleosomes to fold into more compact chromatin structures. However, the in vivo roles of H1 are poorly understood2. Here we show that the local density of H1 controls the balance of repressive and active chromatin domains by promoting genomic compaction. We generated a conditional triple-H1-knockout mouse strain and depleted H1 in haematopoietic cells. H1 depletion in T cells leads to de-repression of T cell activation genes, a process that mimics normal T cell activation. Comparison of chromatin structure in normal and H1-depleted CD8+ T cells reveals that H1-mediated chromatin compaction occurs primarily in regions of the genome containing higher than average levels of H1: the chromosome conformation capture (Hi-C) B compartment and regions of the Hi-C A compartment marked by PRC2. Reduction of H1 stoichiometry leads to decreased H3K27 methylation, increased H3K36 methylation, B-to-A-compartment shifting and an increase in interaction frequency between compartments. In vitro, H1 promotes PRC2-mediated H3K27 methylation and inhibits NSD2-mediated H3K36 methylation. Mechanistically, H1 mediates these opposite effects by promoting physical compaction of the chromatin substrate. Our results establish H1 as a critical regulator of gene silencing through localized control of chromatin compaction, 3D genome organization and the epigenetic landscape.


Asunto(s)
Ensamble y Desensamble de Cromatina , Cromatina/genética , Epigénesis Genética , Histonas/metabolismo , Animales , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular/genética , Cromatina/química , Cromatina/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Femenino , Silenciador del Gen , Histonas/química , Activación de Linfocitos/genética , Masculino , Metilación , Ratones , Ratones Noqueados
2.
Genes Dev ; 31(6): 603-616, 2017 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-28404631

RESUMEN

Eukaryotic DNA replicates asynchronously, with discrete genomic loci replicating during different stages of S phase. Drosophila larval tissues undergo endoreplication without cell division, and the latest replicating regions occasionally fail to complete endoreplication, resulting in underreplicated domains of polytene chromosomes. Here we show that linker histone H1 is required for the underreplication (UR) phenomenon in Drosophila salivary glands. H1 directly interacts with the Suppressor of UR (SUUR) protein and is required for SUUR binding to chromatin in vivo. These observations implicate H1 as a critical factor in the formation of underreplicated regions and an upstream effector of SUUR. We also demonstrate that the localization of H1 in chromatin changes profoundly during the endocycle. At the onset of endocycle S (endo-S) phase, H1 is heavily and specifically loaded into late replicating genomic regions and is then redistributed during the course of endoreplication. Our data suggest that cell cycle-dependent chromosome occupancy of H1 is governed by several independent processes. In addition to the ubiquitous replication-related disassembly and reassembly of chromatin, H1 is deposited into chromatin through a novel pathway that is replication-independent, rapid, and locus-specific. This cell cycle-directed dynamic localization of H1 in chromatin may play an important role in the regulation of DNA replication timing.


Asunto(s)
Cromatina/metabolismo , Drosophila/genética , Endorreduplicación , Histonas/metabolismo , Animales , Proteínas de Unión al ADN/metabolismo , Drosophila/crecimiento & desarrollo , Proteínas de Drosophila/metabolismo , Heterocromatina/metabolismo , Larva/genética , Larva/metabolismo , Fase S/genética , Glándulas Salivales/metabolismo
3.
Proc Natl Acad Sci U S A ; 116(36): 17841-17847, 2019 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-31431533

RESUMEN

Pu.1 is an ETS family transcription factor (TF) that plays critical roles in erythroid progenitors by promoting proliferation and blocking terminal differentiation. However, the mechanisms controlling expression and down-regulation of Pu.1 during early erythropoiesis have not been defined. In this study, we identify the actions of Runx1 and Pu.1 itself at the Pu.1 gene Upstream Regulatory Element (URE) as major regulators of Pu.1 expression in Burst-Forming Unit erythrocytes (BFUe). During early erythropoiesis, Runx1 and Pu.1 levels decline, and chromatin accessibility at the URE is lost. Ectopic expression of Runx1 or Pu.1, both of which bind the URE, prevents Pu.1 down-regulation and blocks terminal erythroid differentiation, resulting in extensive ex vivo proliferation and immortalization of erythroid progenitors. Ectopic expression of Runx1 in BFUe lacking a URE fails to block terminal erythroid differentiation. Thus, Runx1, acting at the URE, and Pu.1 itself directly regulate Pu.1 levels in erythroid cells, and loss of both factors is critical for Pu.1 down-regulation during terminal differentiation. The molecular mechanism of URE inactivation in erythroid cells through loss of TF binding represents a distinct pattern of Pu.1 regulation from those described in other hematopoietic cell types such as T cells which down-regulate Pu.1 through active repression. The importance of down-regulation of Runx1 and Pu.1 in erythropoiesis is further supported by genome-wide analyses showing that their DNA-binding motifs are highly overrepresented in regions that lose chromatin accessibility during early erythroid development.


Asunto(s)
Diferenciación Celular/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Células Precursoras Eritroides/citología , Células Precursoras Eritroides/metabolismo , Regulación de la Expresión Génica , Proteínas Proto-Oncogénicas/genética , Transactivadores/genética , Animales , Cromatina/genética , Cromatina/metabolismo , Eritropoyesis/genética , Ratones , Células RAW 264.7 , Elementos de Respuesta , Transcripción Genética
4.
Med Sci Sports Exerc ; 44(7): 1344-50, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22217570

RESUMEN

INTRODUCTION: Although both humans and quadrupeds frequently coordinate breathing and limb movement during running, early studies in humans focused on how increased breathing flexibility in humans allowed for relaxed or even transient coordination during locomotion. This difference was used to explain why quadrupeds had an optimal running speed whereas humans did not. Recent research, however, has clearly demonstrated that humans, like quadrupeds, have an optimal running speed. Because these findings are new, it remains unclear why this is true: whether because entrainment in humans was more important than initially predicted or because another restraint is acting. Here, we try to explain the observed minimum cost of transport (CoT) by analyzing metabolic cost with respect to entrainment and a standard set of anthropometrics. METHODS: We measured the energetic cost of human running at five different speeds and calculated individual CoT curves for each participant (N = 9). Simultaneously, entrainment was determined by the degree to which a poststimulus histogram (breaths per 0.05-s bin after a footfall) differed from a uniform plot. RESULTS: We compared the degree of entrainment to each participant's optimal running speed and found that although all of our subjects clearly entrained at some speeds, entrainment was not a function of CoT (P = 0.897). Because entrainment was also not correlated with speed (P = 0.304), it seems that bipedalism removed the respiratory constraints associated with quadrupedalism as originally suggested. CONCLUSIONS: Unlike quadrupeds, for whom respiratory constraints remain implicated in the speed dependence of CoT, constraints that lead to a minimum CoT for people must involve other mechanisms of efficiency such as the storage and release of energy in the lower limbs.


Asunto(s)
Aptitud Física/fisiología , Respiración , Carrera/fisiología , Carrera/normas , Antropometría , Fenómenos Biomecánicos , Femenino , Humanos , Masculino , Metabolismo/fisiología , Consumo de Oxígeno/fisiología , Adulto Joven
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