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Charting a dynamic DNA methylation landscape of the human genome
DNA methylation is a defining feature of mammalian cellular identity and essential for normal development1,2. Most cell types, except germ cells and pre-implantation embryos3â5, display relatively stable DNA methylation patterns with 70â80% of all CpGs being methylated6. Despite recent advances we still have a too limited understanding of when, where and how many CpGs participate in genomic regulation. Here we report the in depth analysis of 42 whole genome bisulfite sequencing (WGBS) data sets across 30 diverse human cell and tissue types. We observe dynamic regulation for only 21.8% of autosomal CpGs within a normal developmental context, a majority of which are distal to transcription start sites. These dynamic CpGs co-localize with gene regulatory elements, particularly enhancers and transcription factor binding sites (TFBS), which allow identification of key lineage specific regulators. In addition, differentially methylated regions (DMRs) often harbor SNPs associated with cell type related diseases as determined by GWAS. The results also highlight the general inefficiency of WGBS as 70â80% of the sequencing reads across these data sets provided little or no relevant information regarding CpG methylation. To further demonstrate the utility of our DMR set, we use it to classify unknown samples and identify representative signature regions that recapitulate major DNA methylation dynamics. In summary, although in theory every CpG can change its methylation state, our results suggest that only a fraction does so as part of coordinated regulatory programs. Therefore our selected DMRs can serve as a starting point to help guide novel, more effective reduced representation approaches to capture the most informative fraction of CpGs as well as further pinpoint putative regulatory elements
Transfer Matrices and Partition-Function Zeros for Antiferromagnetic Potts Models. V. Further Results for the Square-Lattice Chromatic Polynomial
We derive some new structural results for the transfer matrix of
square-lattice Potts models with free and cylindrical boundary conditions. In
particular, we obtain explicit closed-form expressions for the dominant (at
large |q|) diagonal entry in the transfer matrix, for arbitrary widths m, as
the solution of a special one-dimensional polymer model. We also obtain the
large-q expansion of the bulk and surface (resp. corner) free energies for the
zero-temperature antiferromagnet (= chromatic polynomial) through order q^{-47}
(resp. q^{-46}). Finally, we compute chromatic roots for strips of widths 9 <=
m <= 12 with free boundary conditions and locate roughly the limiting curves.Comment: 111 pages (LaTeX2e). Includes tex file, three sty files, and 19
Postscript figures. Also included are Mathematica files data_CYL.m and
data_FREE.m. Many changes from version 1: new material on series expansions
and their analysis, and several proofs of previously conjectured results.
Final version to be published in J. Stat. Phy
Transfer matrices and partition-function zeros for antiferromagnetic Potts models. VI. Square lattice with special boundary conditions
We study, using transfer-matrix methods, the partition-function zeros of the
square-lattice q-state Potts antiferromagnet at zero temperature (=
square-lattice chromatic polynomial) for the special boundary conditions that
are obtained from an m x n grid with free boundary conditions by adjoining one
new vertex adjacent to all the sites in the leftmost column and a second new
vertex adjacent to all the sites in the rightmost column. We provide numerical
evidence that the partition-function zeros are becoming dense everywhere in the
complex q-plane outside the limiting curve B_\infty(sq) for this model with
ordinary (e.g. free or cylindrical) boundary conditions. Despite this, the
infinite-volume free energy is perfectly analytic in this region.Comment: 114 pages (LaTeX2e). Includes tex file, three sty files, and 23
Postscript figures. Also included are Mathematica files data_Eq.m,
data_Neq.m,and data_Diff.m. Many changes from version 1, including several
proofs of previously conjectured results. Final version to be published in J.
Stat. Phy
lincRNAs act in the circuitry controlling pluripotency and differentiation
Although thousands of large intergenic non-coding RNAs (lincRNAs) have been identified in mammals, few have been functionally characterized, leading to debate about their biological role. To address this, we performed loss-of-function studies on most lincRNAs expressed in mouse embryonic stem (ES) cells and characterized the effects on gene expression. Here we show that knockdown of lincRNAs has major consequences on gene expression patterns, comparable to knockdown of well-known ES cell regulators. Notably, lincRNAs primarily affect gene expression in trans. Knockdown of dozens of lincRNAs causes either exit from the pluripotent state or upregulation of lineage commitment programs. We integrate lincRNAs into the molecular circuitry of ES cells and show that lincRNA genes are regulated by key transcription factors and that lincRNA transcripts bind to multiple chromatin regulatory proteins to affect shared gene expression programs. Together, the results demonstrate that lincRNAs have key roles in the circuitry controlling ES cell state.Broad InstituteHarvard UniversityNational Human Genome Research Institute (U.S.)Merkin Family Foundation for Stem Cell Researc
Bioavailability, distribution and clearance of tracheally-instilled and gavaged uncoated or silica-coated zinc oxide nanoparticles
Comparison of selenophene and thienothiophene incorporation into pentacyclic lactam-based conjugated polymers for organic solar cells
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