The past decade has highlighted the central role of epigenetic processes in cancer causation, progression and treatment. Next-generation sequencing is providing a window for visualizing the human epigenome and how it is altered in cancer. This view provides many surprises, including linking epigenetic abnormalities to mutations in genes that control DNA methylation, the packaging and the function of DNA in chromatin, and metabolism. Epigenetic alterations are leading candidates for the development of specific markers for cancer detection, diagnosis and prognosis. The enzymatic processes that control the epigenome present new opportunities for deriving therapeutic strategies designed to reverse transcriptional abnormalities that are inherent to the cancer epigenome.

http://sdjohnston.faculty.noctrl.edu/360/Cancer%20Epigenome.pdf

A decade of exploring the cancer epigenome — biological and translational implications

BACKGROUND Living cells contain distinct subcompartments to facilitate spatiotemporal regulation of biological reactions. In addition to canonical membrane-bound organelles such as secretory vesicles and endoplasmic reticulum, there are many organelles that do not have an enclosing membrane yet remain coherent structures that can compartmentalize and concentrate specific sets of molecules. Examples include assemblies in the nucleus such as the nucleolus, Cajal bodies, and nuclear speckles and also cytoplasmic structures such as stress granules, P-bodies, and germ granules. These structures play diverse roles in various biological processes and are also increasingly implicated in protein aggregation diseases. ADVANCES A number of studies have shown that membrane-less assemblies exhibit remarkable liquid-like features. As with conventional liquids, they typically adopt round morphologies and coalesce into a single droplet upon contact with one another and also wet intracellular surfaces such as the nuclear envelope. Moreover, component molecules exhibit dynamic exchange with the surrounding nucleoplasm and cytoplasm. These findings together suggest that these structures represent liquid-phase condensates, which form via a biologically regulated (liquid-liquid) phase separation process. Liquid phase condensation increasingly appears to be a fundamental mechanism for organizing intracellular space. Consistent with this concept, several membrane-less organelles have been shown to exhibit a concentration threshold for assembly, a hallmark of phase separation. At the molecular level, weak, transient interactions between molecules with multivalent domains or intrinsically disordered regions (IDRs) are a driving force for phase separation. In cells, condensation of liquid-phase assemblies can be regulated by active processes, including transcription and various posttranslational modifications. The simplest physical picture of a homogeneous liquid phase is often not enough to capture the full complexity of intracellular condensates, which frequently exhibit heterogeneous multilayered structures with partially solid-like characters. However, recent studies have shown that multiple distinct liquid phases can coexist and give rise to richly structured droplet architectures determined by the relative liquid surface tensions. Moreover, solid-like phases can emerge from metastable liquid condensates via multiple routes of potentially both kinetic and thermodynamic origins, which has important implications for the role of intracellular liquids in protein aggregation pathologies. OUTLOOK The list of intracellular assemblies driven by liquid phase condensation is growing rapidly, but our understanding of their sequence-encoded biological function and dysfunction lags behind. Moreover, unlike equilibrium phases of nonliving matter, living cells are far from equilibrium, with intracellular condensates subject to various posttranslational regulation and other adenosine triphosphate–dependent biological activity. Efforts using in vitro reconstitution, combined with traditional cell biology approaches and quantitative biophysical tools, are required to elucidate how such nonequilibrium features of living cells control intracellular phase behavior. The functional consequences of forming liquid condensates are likely multifaceted and may include facilitated reaction, sequestration of specific factors, and organization of associated intracellular structures. Liquid phase condensation is particularly interesting in the nucleus, given the growing interest in the impact of nuclear phase behavior on the flow of genetic information; nuclear condensates range from micrometer-sized bodies such as the nucleolus to submicrometer structures such as transcriptional assemblies, all of which directly interact with and regulate the genome. Deepening our understanding of these intracellular states of matter not only will shed light on the basic biology of cellular organization but also may enable therapeutic intervention in protein aggregation disease by targeting intracellular phase behavior.

Liquid phase condensation in cell physiology and disease.

http://www.uniroma2.it/didattica/Genomica_BTI/deposito/Mamm_Epigenome_rev_Cell.pdf

The mammalian epigenome.

http://basicmed.med.ncku.edu.tw/admin/up_img/970513-3.pdf

A Chromatin Landmark and Transcription Initiation at Most Promoters in Human Cells

http://baldwinlab.chem.ox.ac.uk/publications/2015TimBlobs.pdf

Phase Transition of a Disordered Nuage Protein Generates Environmentally Responsive Membraneless Organelles

https://www.cell.com/developmental-cell/pdf/S1534-5807(05)00421-1.pdf

Hyperdynamic Plasticity of Chromatin Proteins in Pluripotent Embryonic Stem Cells

Despite major advances in understanding the pathophysiology of hypertension and availability of effective and safe antihypertensive drugs, suboptimal blood pressure (BP) control is still the most important risk factor for cardiovascular mortality and is globally responsible for more than 7 million deaths annually. Short-term and long-term BP regulation involve the integrated actions of multiple cardiovascular, renal, neural, endocrine, and local tissue control systems. Clinical and experimental observations strongly support a central role for the kidneys in the long-term regulation of BP, and abnormal renal-pressure natriuresis is present in all forms of chronic hypertension. Impaired renal-pressure natriuresis and chronic hypertension can be caused by intrarenal or extrarenal factors that reduce glomerular filtration rate or increase renal tubular reabsorption of salt and water; these factors include excessive activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, increased formation of reactive oxygen species, endothelin, and inflammatory cytokines, or decreased synthesis of nitric oxide and various natriuretic factors. In human primary (essential) hypertension, the precise causes of impaired renal function are not completely understood, although excessive weight gain and dietary factors appear to play a major role since hypertension is rare in nonobese hunter-gathers living in nonindustrialized societies. Recent advances in genetics offer opportunities to discover gene-environment interactions that may also contribute to hypertension, although success thus far has been limited mainly to identification of rare monogenic forms of hypertension.

Hypertension: physiology and pathophysiology.

Endothelin: key mediator of hypertension in preeclampsia

Despite being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of pre-eclampsia have yet to be fully elucidated. However, it is evident that this is a complex disorder involving multiple organ systems, and by using integrative approaches, enormous progress has been made towards understanding the pathophysiology of pre-eclampsia. Growing evidence supports the concept that the placenta plays a central role in the pathogenesis of pre-eclampsia and that reduced uteroplacental perfusion, which develops as a result of abnormal cytotrophoblast invasion of spiral arterioles, triggers the cascade of events leading to the maternal disorder. Placental ischaemia leads to release of soluble placental factors, many of which are classified as anti-angiogenic or pro-inflammatory. Once these ischaemic placental factors reach the maternal circulation, they cause widespread activation and dysfunction of the maternal vascular endothelium that results in enhanced formation of endothelin-1 and superoxide, increased vascular sensitivity to angiotensin II and decreased formation of vasodilators such as nitric oxide. This review highlights these links between placental ischaemia, maternal endothelial activation and renal dysfunction in the pathogenesis of hypertension in pre-eclampsia.

Pathophysiology of hypertension in pre-eclampsia: a lesson in integrative physiology

Preeclampsia, a pregnancy specific disorder, is typically defined as new-onset hypertension presenting after the 20th week of gestation with proteinuria. The overall prevalence in the United States is 3% to 8% with higher incidence in specific ethnic subpopulations, notably blacks. Preeclampsia is a major source of maternal and neonatal morbidity and mortality. Moreover, women who endure preeclampsia are at greater risk of cardiovascular diseases later in life. Studies published in Hypertension and other journals during the last few years have provided new insights not only into potential mechanisms underlying the pathophysiology of preeclampsia but also into the identification of potential biomarkers for the early diagnosis of preeclampsia. Although numerous factors have been implicated in the pathophysiology of preeclampsia, the main focus of this Recent Advances article is to review recent studies that link placental ischemia, endothelial and vascular dysfunction, and hypertension in preeclampsia.

Despite intense research into the identification of molecular markers of preeclampsia, a reliable and accurate marker for the early diagnosis of preeclampsia remains elusive. A number of recent articles have suggested markers that could prove useful in the diagnosis of the disorder. With the growing interest in autoimmunity in preeclampsia, several studies have looked at immune factors in the maternal circulation as possible biomarkers. For instance, Siddiqui et al1 found widespread (≈95%) presence of agonistic autoantibodies to the angiotensin type-1 receptor (AT1-AA). Additionally, the levels of these autoantibodies correlated well with the degree of disease severity, suggesting potential use in diagnosis. In a related study, Jensen et al2 found that CD19(+)CD5(+) B-cell populations, a potential source for the AT1-AA, are significantly elevated in the maternal circulation of patients with preeclampsia during late gestation when compared with normal-pregnant controls at the same gestational stage.

One of the most active areas of research in preeclampsia is angiogenic …

Eric M. George

Papers

Hyperdynamic Plasticity of Chromatin Proteins in Pluripotent Embryonic Stem Cells

Hypertension: physiology and pathophysiology.

Endothelin: key mediator of hypertension in preeclampsia

Pathophysiology of hypertension in pre-eclampsia: a lesson in integrative physiology

Recent Advances in the Understanding of the Pathophysiology of Preeclampsia