A solution
to the classic unsolved problem of olefin hydromethylation
is presented. This highly chemoselective method can tolerate labile
and reactive chemical functionalities and uses a simple set of reagents.
An array of olefins, including mono-, di-, and trisubstituted olefins,
are all smoothly hydromethylated. This mild protocol can be used to
simplify the synthesis of a specific target or to directly “edit”
complex natural products and other advanced materials. The method
is also amenable to the simple installation of radioactive and stable
labeled methyl groups.
Mammalian SWI/SNF (mSWI/SNF) adenosine triphosphate–dependent chromatin remodelers modulate genomic architecture and gene expression and are frequently mutated in disease. However, the specific chromatin features that govern their nucleosome binding and remodeling activities remain unknown. We subjected endogenously purified mSWI/SNF complexes and their constituent assembly modules to a diverse library of DNA-barcoded mononucleosomes, performing more than 25,000 binding and remodeling measurements. Here, we define histone modification-, variant-, and mutation-specific effects, alone and in combination, on mSWI/SNF activities and chromatin interactions. Further, we identify the combinatorial contributions of complex module components, reader domains, and nucleosome engagement properties to the localization of complexes to selectively permissive chromatin states. These findings uncover principles that shape the genomic binding and activity of a major chromatin remodeler complex family.
Highlights d A conserved SMARCB1 C-terminal a helix binds the nucleosome acidic patch d Recurrent point mutations disrupt this interaction and mSWI/ SNF nucleosome remodeling d The SMARCB1 CTD is dispensable for genome-wide BAF complex targeting d Heterozygous SMARCB1 mutations impede Ngn2-mediated neuronal differentiation
Recent studies have implicated the nucleosome acidic patch in the activity of ATP-dependent chromatin remodeling machines. We employed a photocrosslinking-based nucleosome profiling technology-'photoscanning'-to identify a conserved basic motif within the catalytic subunit of ISWI remodelers, SNF2h, which engages this nucleosomal epitope. This region of SNF2h is essential for chromatin remodeling activity in a reconstituted biochemical system and in cells. Our studies suggest that the basic motif in SNF2h plays a critical role in anchoring the remodeler to the nucleosomal surface. We also examine the functional consequences of several cancer-associated histone mutations that map to the nucleosome acidic patch. Kinetic studies employing physiologically relevant heterotypic nucleosomal substrates ('Janus' nucleosomes) indicate that these cancer mutations can disrupt regularly spaced chromatin structure by inducing ISWImediated unidirectional nucleosome sliding. These results imply a potential mechanistic link between oncogenic histones and alterations to the chromatin landscape. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
The utility of quinone diazides in materials science is vast and well-documented, yet this potentially useful motif has languished in the annals of organic synthesis. Herein we show that modern tools of catalysis can be employed with free or suitably masked quinone diazides to unleash the power of these classic diazo compounds in the context of both inter- and intramolecular olefin cyclopropanation.
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