Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome.

Eukaryotic gene transcription is accompanied by acetylation and methylation of nucleosomes near promoters, but the locations and roles of histone modifications elsewhere in the genome remain unclear. We determined the chromatin modification states in high resolution along 30 Mb of the human genome and found that active promoters are marked by trimethylation of Lys4 of histone H3 (H3K4), whereas enhancers are marked by monomethylation, but not trimethylation, of H3K4. We developed computational algorithms using these distinct chromatin signatures to identify new regulatory elements, predicting over 200 promoters and 400 enhancers within the 30-Mb region. This approach accurately predicted the location and function of independently identified regulatory elements with high sensitivity and specificity and uncovered a novel functional enhancer for the carnitine transporter SLC22A5 (OCTN2). Our results give insight into the connections between chromatin modifications and transcriptional regulatory activity and provide a new tool for the functional annotation of the human genome.

Histone modifications at human enhancers reflect global cell-type-specific gene expression.

The human body is composed of diverse cell types with distinct functions. Although it is known that lineage specification depends on cell-specific gene expression, which in turn is driven by promoters, enhancers, insulators and other cis-regulatory DNA sequences for each gene, the relative roles of these regulatory elements in this process are not clear. We have previously developed a chromatin-immunoprecipitation-based microarray method (ChIP-chip) to locate promoters, enhancers and insulators in the human genome. Here we use the same approach to identify these elements in multiple cell types and investigate their roles in cell-type-specific gene expression. We observed that the chromatin state at promoters and CTCF-binding at insulators is largely invariant across diverse cell types. In contrast, enhancers are marked with highly cell-type-specific histone modification patterns, strongly correlate to cell-type-specific gene expression programs on a global scale, and are functionally active in a cell-type-specific manner. Our results define over 55,000 potential transcriptional enhancers in the human genome, significantly expanding the current catalogue of human enhancers and highlighting the role of these elements in cell-type-specific gene expression.

A Digital Ecosystem of Diabetes Data and Technology: Services, Systems, and Tools Enabled by Wearables, Sensors, and Apps.

The management of type 1 diabetes (T1D) ideally involves regimented measurement of various health signals; constant interpretation of diverse kinds of data; and consistent cohesion between patients, caregivers, and health care professionals (HCPs). In the context of myriad factors that influence blood glucose dynamics for each individual patient (eg, medication, activity, diet, stress, sleep quality, hormones, environment), such coordination of self-management and clinical care is a great challenge, amplified by the routine unavailability of many types of data thought to be useful in diabetes decision-making. While much remains to be understood about the physiology of diabetes and blood glucose dynamics at the level of the individual, recent and emerging medical and consumer technologies are helping the diabetes community to take great strides toward truly personalized, real-time, data-driven management of this chronic disease. This review describes "connected" technologies--such as smartphone apps, and wearable devices and sensors--which comprise part of a new digital ecosystem of data-driven tools that can link patients and their care teams for precision management of diabetes. These connected technologies are rich sources of physiologic, behavioral, and contextual data that can be integrated and analyzed in "the cloud" for research into personal models of glycemic dynamics, and employed in a multitude of applications for mobile health (mHealth) and telemedicine in diabetes care.

Nocturnal continuous glucose and sleep stage data in adults with type 1 diabetes in real-world conditions.

BACKGROUND: Sleep plays an important role in health, and poor sleep is associated with negative impacts on diabetes management, but few studies have objectively evaluated sleep in adults with type 1 diabetes mellitus (T1DM). Nocturnal glycemia and sleep characteristics in T1DM were evaluated using body-worn sensors in real-world conditions. METHODS: Analyses were performed on data collected by the Diabetes Management Integrated Technology Research Initiative pilot study of 17 T1DM subjects: 10 male, 7 female; age 19-61 years; T1DM duration 14.9 ± 11.0 years; hemoglobin A1c (HbA1c) 7.3% ± 1.3% (mean ± standard deviation). Each subject was equipped with a continuous glucose monitor and a wireless sleep monitor (WSM) for four nights. Sleep stages [rapid eye movement (REM), light, and deep sleep] were continuously recorded by the WSM. Nocturnal glycemia (mg/dl) was evaluated as hypoglycemia (<50 mg/dl), low (50-69 mg/dl), euglycemia (70-120 mg/dl), high (121-250 mg/dl), and hyperglycemia (>250 mg/dl) and by several indices of glycemic variability. Glycemia was analyzed within each sleep stage. RESULTS: Subjects slept 358 ± 48 min per night, with 85 ± 27 min in REM sleep, 207 ± 42 min in light sleep, and 66 ± 30 min in deep sleep (mean ± standard deviation). Increased time in deep sleep was associated with lower HbA1c (R2 = 0.42; F = 9.37; p < .01). Nocturnal glycemia varied widely between and within subjects. Glycemia during REM sleep was hypoglycemia 5.5% ± 18.1%, low 6.6% ± 18.5%, euglycemia 44.6% ± 39.5%, high 37.9% ± 39.7%, and hyperglycemia 5.5% ± 21.2%; glycemia during light sleep was hypoglycemia 4.8% ± 12.4%, low 7.3% ± 12.9%, euglycemia 42.1% ± 33.7%, high 39.2% ± 34.6%, and hyperglycemia 6.5% ± 20.5%; and glycemia during deep sleep was hypoglycemia 0.5% ± 2.2%, low 5.8% ± 14.3%, euglycemia 48.0% ± 37.5%, high 39.5% ± 37.6%, and hyperglycemia 6.2% ± 19.5%. Significantly less time was spent in the hypoglycemic range during deep sleep compared with light sleep (p = .02). CONCLUSIONS: Increased time in deep sleep was associated with lower HbA1c, and less hypoglycemia occurred in deep sleep in T1DM, though this must be further evaluated in larger subsequent studies. Furthermore, the consumer-grade WSM device was useful for objectively studying sleep in a real-world setting.

iDASH: integrating data for analysis, anonymization, and sharing.

iDASH (integrating data for analysis, anonymization, and sharing) is the newest National Center for Biomedical Computing funded by the NIH. It focuses on algorithms and tools for sharing data in a privacy-preserving manner. Foundational privacy technology research performed within iDASH is coupled with innovative engineering for collaborative tool development and data-sharing capabilities in a private Health Insurance Portability and Accountability Act (HIPAA)-certified cloud. Driving Biological Projects, which span different biological levels (from molecules to individuals to populations) and focus on various health conditions, help guide research and development within this Center. Furthermore, training and dissemination efforts connect the Center with its stakeholders and educate data owners and data consumers on how to share and use clinical and biological data. Through these various mechanisms, iDASH implements its goal of providing biomedical and behavioral researchers with access to data, software, and a high-performance computing environment, thus enabling them to generate and test new hypotheses.

Finding distal regulatory elements in the human genome.

Transcriptional regulation of human genes depends not only on promoters and nearby cis-regulatory elements, but also on distal regulatory elements such as enhancers, insulators, locus control regions, and silencing elements, which are often located far away from the genes they control. Our knowledge of human distal regulatory elements is very limited, but the last several years have seen rapid progress in the development of strategies to identify these long-range regulatory sequences throughout the human genome. Here, we review these advances, focusing on two important classes of distal regulatory sequences-enhancers and insulators.