Eukaryotic genomes are packaged into nucleosome particles that occlude the DNA from interacting with most DNA binding proteins. Nucleosomes have higher affinity for particular DNA sequences, reflecting the ability of the sequence to bend sharply, as required by the nucleosome structure. However, it is not known whether these sequence preferences have a significant influence on nucleosome position in vivo, and thus regulate the access of other proteins to DNA. Here we isolated nucleosome-bound sequences at high resolution from yeast and used these sequences in a new computational approach to construct and validate experimentally a nucleosome–DNA interaction model, and to predict the genome-wide organization of nucleosomes. Our results demonstrate that genomes encode an intrinsic nucleosome organization and that this intrinsic organization can explain ∼50% of the in vivo nucleosome positions. This nucleosome positioning code may facilitate specific chromosome functions including transcription factor binding, transcription initiation, and even remodelling of the nucleosomes themselves.

http://absimage.aps.org/image/MAR08/MWS_MAR08-2008-020581.pdf

The Genomic Code for Nucleosome Positioning

The GABAergic neurotransmission is a highly conserved system that has been attributed to various regulatory events. There has been a notable number of studies on the importance of GABAergic neurotrans

/pdf/epigenetic-regulations-of-gabaergic-neurotransmission-5aszwmn24m.pdf

Epigenetic Regulations of GABAergic Neurotransmission: Relevance for Neurological Disorders and Epigenetic Therapy

https://www.cell.com/cell-stem-cell/pdf/S1934-5909(15)00267-2.pdf

Stem Cell Therapies in Clinical Trials: Progress and Challenges

Traumatic spinal cord injury (SCI) has devastating consequences for the physical, social and vocational well-being of patients. The demographic of SCIs is shifting such that an increasing proportion of older individuals are being affected. Pathophysiologically, the initial mechanical trauma (the primary injury) permeabilizes neurons and glia and initiates a secondary injury cascade that leads to progressive cell death and spinal cord damage over the subsequent weeks. Over time, the lesion remodels and is composed of cystic cavitations and a glial scar, both of which potently inhibit regeneration. Several animal models and complementary behavioural tests of SCI have been developed to mimic this pathological process and form the basis for the development of preclinical and translational neuroprotective and neuroregenerative strategies. Diagnosis requires a thorough patient history, standardized neurological physical examination and radiographic imaging of the spinal cord. Following diagnosis, several interventions need to be rapidly applied, including haemodynamic monitoring in the intensive care unit, early surgical decompression, blood pressure augmentation and, potentially, the administration of methylprednisolone. Managing the complications of SCI, such as bowel and bladder dysfunction, the formation of pressure sores and infections, is key to address all facets of the patient's injury experience.

/pdf/traumatic-spinal-cord-injury-16z1ghwuah.pdf

Traumatic spinal cord injury

Histone modifications are key epigenetic regulatory features that have important roles in many cellular events. Lysine methylations mark various sites on the tail and globular domains of histones and their levels are precisely balanced by the action of methyltransferases (‘writers’) and demethylases (‘erasers’). In addition, distinct effector proteins (‘readers’) recognize specific methyl-lysines in a manner that depends on the neighboring amino-acid sequence and methylation state. Misregulation of histone lysine methylation has been implicated in several cancers and developmental defects. Therefore, histone lysine methylation has been considered a potential therapeutic target, and clinical trials of several inhibitors of this process have shown promising results. A more detailed understanding of histone lysine methylation is necessary for elucidating complex biological processes and, ultimately, for developing and improving disease treatments. This review summarizes enzymes responsible for histone lysine methylation and demethylation and how histone lysine methylation contributes to various biological processes. Elucidating how enzymes add and subtract methyl groups to the proteins that package DNA could lead to new disease treatments. In a review article, Jaehoon Kim and colleagues from the Korea Advanced Institute of Science and Technology in Daejeon, South Korea, summarize the mechanisms by which histone proteins, which assemble to form spool-like complexes around which DNA wraps into more compact units, are modified and how misregulation of this process can lead to cancer, developmental defects and other health problems. The authors focus on how methyl groups are added to and removed from residues of the amino acid lysine within histone proteins. They liken certain enzymes to writers, erasers and readers of histone lysine methylation, and make the case that these enzymes should be investigated as potential therapeutic targets.

/pdf/writing-erasing-and-reading-histone-lysine-methylations-3rnlvgubc1.pdf

Writing, erasing and reading histone lysine methylations

Histone-lysine N-methyltransferase 2 (KMT2) family proteins methylate lysine 4 on the histone H3 tail at important regulatory regions in the genome and thereby impart crucial functions through modulating chromatin structures and DNA accessibility. Although the human KMT2 family was initially named the mixed-lineage leukaemia (MLL) family, owing to the role of the first-found member KMT2A in this disease, recent exome-sequencing studies revealed KMT2 genes to be among the most frequently mutated genes in many types of human cancers. Efforts to integrate the molecular mechanisms of KMT2 with its roles in tumorigenesis have led to the development of first-generation inhibitors of KMT2 function, which could become novel cancer therapies.

/pdf/hijacked-in-cancer-the-kmt2-mll-family-of-methyltransferases-tn4bua2z8r.pdf

Hijacked in cancer: the KMT2 (MLL) family of methyltransferases

Over the last decade, human cell transplantation and neural stem cell trials have examined the feasibility and safety of these potential therapies for treatment of a variety of neurological disorders. However, significant safety concerns have surrounded these trials due to the possibility of ectopic, uncontrolled cellular growth and tumor formation. The authors present the case of an 18-year-old woman who sustained a complete spinal cord injury at T10-11. Three years after injury, she remained paraplegic and underwent olfactory mucosal cell implantation at the site of injury. She developed back pain 8 years later, and imaging revealed an intramedullary spinal cord mass at the site of cell implantation, which required resection. Intraoperative findings revealed an expanded spinal cord with a multicystic mass containing large amounts of thick mucus-like material. Histological examination and immunohistochemical staining revealed that the mass was composed mostly of cysts lined by respiratory epithelium, submucosal glands with goblet cells, and intervening nerve twigs. This is the first report of a human spinal cord mass complicating spinal cord cell transplantation and neural stem cell therapy. Given the prolonged time to presentation, safety monitoring of all patients with cell transplantation and neural stem cell implantation should be maintained for many years.

/pdf/autograft-derived-spinal-cord-mass-following-olfactory-1khy6sh1n5.pdf

Autograft-derived spinal cord mass following olfactory mucosal cell transplantation in a spinal cord injury patient: Case report.

Ultra-Widefield Steering-Based Spectral-Domain Optical Coherence Tomography Imaging of the Retinal Periphery

// Andi K. Cani 1, 2 , Daniel H. Hovelson 1, 3 , Hakan Demirci 4 , Mark W. Johnson 4 , Scott A. Tomlins 1, 2, 5, 6, 7 , Rajesh C. Rao 2, 4, 6, 7, 8 1 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, US 2 Department of Pathology, University of Michigan, Ann Arbor, MI, US 3 Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, US 4 Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, US 5 Department of Urology, University of Michigan, Ann Arbor, MI, US 6 Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, US 7 A. Alfred Taubman Medical Research Institute, University of Michigan, Ann Arbor, MI, US 8 Section of Ophthalmology, Surgical Service, Veterans Administration Ann Arbor, Healthcare System, Ann Arbor, MI, US Correspondence to: Scott A. Tomlins, email: tomlinss@umich.edu Rajesh C. Rao, email: rajeshr@umich.edu Keywords: next generation sequencing, vitreoretinal lymphoma, primary central nervous system lymphoma, biopsy, precision medicine Received: November 21, 2016      Accepted: November 23, 2016      Published: December 17, 2016 ABSTRACT Background: Vitreoretinal lymphoma (VRL), the most common lymphoma of the eye, is a rare form of primary CNS lymphoma (PCNSL). Most frequently a high-grade diffuse large B cell lymphoma, VRL can cause vision loss and its prognosis remains dismal: the overall survival time is 3 years after diagnosis. Radiotherapy and chemotherapy are used but remain frequently ineffective, and no standardized treatment regimen exists. Furthermore, no biologically targeted treatments, based on the genetic profile of the tumor, are available, as VRL has hitherto not comprehensively been profiled. To address these unmet needs, we hypothesized that a next generation sequencing (NGS)-based, National Cancer Institute (NCI) MATCH Trial-modified panel would be able to identify actionable genomic alterations from small-volume, intraocular liquid biopsies. Methods and Findings: In this retrospective study, we collected diluted vitreous biopsies from 4 patients with a high suspicion for VRL. Following cytological confirmation of lymphoma (all were diffuse large B cell lymphomas), we subjected genomic DNA from the biopsies to NGS, using a panel containing 126 genes (3,435 amplicons across several hotspots per gene), which was modified from that of the NCI MATCH Trial, a new trial that has matched patients with cancers that have not responded (or never responded), to investigational therapeutics based on their prioritized mutation profile rather than site of tumor origin. Using a validated bioinformatics pipeline, we assessed for the presence of actionable mutations and copy number alterations. In all four small-volume, intraocular liquid biopsies, we obtained sufficient genomic DNA for analysis, even in diluted samples in which the undiluted vitreous was used for cytology and flow cytometry. Using NGS, we found targetable heterozygous gain-of-function mutations in the MYD88 oncogene, and confirmed in our cohort the presence the L265 mutations, previously described using PCR-based assays. For the first time in VRL, we also identified the MYD88 S243N mutation. We also identified two-copy copy number losses in the tumor suppressor CDKN2A in all four cases, and one copy loss of the tumor suppressor PTEN in one sample. In one case, in which vitreous biopsies were originally read as cytologically negative, but which was confirmed as lymphoma when a lesion appeared in the brain two years later, our NGS-based approach detected tumoral DNA in the banked, original liquid biopsy. Conclusions: We performed the first systematic exploration of the actionable cancer genome in VRL. Our NGS-based approach identified exploitable genomic alterations such as gain-of-function MYD88 oncogene mutations and loss of the tumor suppressor CDKN2A , and thus illuminates new routes to biologically targeted therapies for VRL, a cancer with a dismal prognosis. This precision medicine strategy could be used to nominate novel, targeted therapies in lymphomas and other blinding and deadly ocular, orbital, and ocular adnexal diseases for which few treatments exist.

/pdf/next-generation-sequencing-of-vitreoretinal-lymphomas-from-4uo3yxhqh4.pdf

Rajesh C. Rao

Papers

Hijacked in cancer: the KMT2 (MLL) family of methyltransferases

Autograft-derived spinal cord mass following olfactory mucosal cell transplantation in a spinal cord injury patient: Case report.

Ultra-Widefield Steering-Based Spectral-Domain Optical Coherence Tomography Imaging of the Retinal Periphery

Next generation sequencing of vitreoretinal lymphomas from small-volume intraocular liquid biopsies: new routes to targeted therapies

MLL1 Inhibition Reprograms Epiblast Stem Cells to Naive Pluripotency