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One or more keywords matched the following properties of Lawrence, Jeanne
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keywords X-chromosome Inactivation
keywords Chromosome Therapy
overview

Non-coding RNA, Repeat Sequences, Heterochromatin Regulation & Nuclear structure: Implications for Disease

Lawrence Lab Website

Research Interests

The Lawrence Lab's research bridges fundamental questions about genome regulation with pursuing the clinical implications of recent advances in the studies of epigenetics. My research interests reflect my inter-disciplinary training in clinical human genetics and fundamental mechanisms of epigenetic regulation.  These interests motivated many years of work to develop new ways to visualize individual genes and RNAs directly within cell structure, particularly in nuclei and chromosomes.  Compelled by a then new idea that gene and chromosome organization was a fundamental component of epigenome programming during development, we developed single-copy gene and nuclear RNA FISH technology, making it possible to map genes not only on chromosomes but within the interphase nucleus.  This early work demonstrated that many “coding” genes and their pre-mRNAs are organized in specific domains or compartments within the mammalian nucleus.  Further developing these approaches in my lab, we demonstrated that RNA from the XIST gene is expressed exclusively from the inactive X-chromosome and coats the structure of the interphase chromosome territory, where it induces heterochromatin modifications which silence the chromosome. These studies were key in establishing the precedent that a large “non-coding” RNA had function, and XIST now remains the preeminent paradigm for RNA regulation of the epigenome and continues to be a focus for my lab’s research. 

Beginning in about 2007, my lab began an ambitious project to translate discoveries in chromosome biology and epigenetics to a novel approach to correct a chromosomal abnormality, particularly trisomy 21 in Down syndrome.  We were able to demonstrate that the very large XIST gene could be accurately targeted into one extra human chromosome 21 in iPS cells from a Down syndrome patient. Further, the RNA showed a robust capacity to repress transcription across the Chr21 bearing XIST.  This paves the way for a number of new avenues for translational research for Down syndrome ongoing in my lab, including the investigation of specific cell pathologies and pathways directly impacted by trisomy in human Down syndrome stem cells (including stem cell derived organoids or “minibrains”) and in Down syndrome mouse models.  This also now opens a new possibility: that trisomy 21 could be functionally corrected in specific cells by insertion of a single gene, XIST.   

The ability of a gene from the X- chromosome to induce silencing of an autosome provides evidence that XIST RNA utilizes a genome-wide mechanism to induce heterochromatin and architectural changes that is shared across chromosomes.   Thus, we are also exploring the implications that many repetitive sequences (often still considered simply evolutionary junk) may play a fundamental role in chromosome structure and function, and in shaping the human epigenome.

 

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Summary Lawrence lab research bridges fundamental questions of developmental epigenetics with translational research into the common problem of chromosome abnormalities, particularly Down syndrome.
One or more keywords matched the following items that are connected to Lawrence, Jeanne
Item TypeName
Academic Article Unbalanced X;autosome translocations provide evidence for sequence specificity in the association of XIST RNA with chromatin.
Academic Article The cell biology of a novel chromosomal RNA: chromosome painting by XIST/Xist RNA initiates a remodeling cascade.
Academic Article The 4q subtelomere harboring the FSHD locus is specifically anchored with peripheral heterochromatin unlike most human telomeres.
Academic Article Ubiquitinated proteins including uH2A on the human and mouse inactive X chromosome: enrichment in gene rich bands.
Academic Article The X chromosome is organized into a gene-rich outer rim and an internal core containing silenced nongenic sequences.
Academic Article An ectopic human XIST gene can induce chromosome inactivation in postdifferentiation human HT-1080 cells.
Academic Article Translating dosage compensation to trisomy 21.
Academic Article Clustering of multiple specific genes and gene-rich R-bands around SC-35 domains: evidence for local euchromatic neighborhoods.
Academic Article Word frequency analysis reveals enrichment of dinucleotide repeats on the human X chromosome and [GATA]n in the X escape region.
Academic Article BRCA1 does not paint the inactive X to localize XIST RNA but may contribute to broad changes in cancer that impact XIST and Xi heterochromatin.
Academic Article X-inactivation reveals epigenetic anomalies in most hESC but identifies sublines that initiate as expected.
Academic Article AURKB-mediated effects on chromatin regulate binding versus release of XIST RNA to the inactive chromosome.
Academic Article Maternal Rnf12/RLIM is required for imprinted X-chromosome inactivation in mice.
Academic Article The three-dimensional folding of the ?-globin gene domain reveals formation of chromatin globules.
Academic Article Paternal RLIM/Rnf12 is a survival factor for milk-producing alveolar cells.
Concept Chromosomes, Human, Pair 16
Concept Chromosomes, Human, Pair 17
Concept Chromosome Banding
Concept Chromosomes, Human, Pair 4
Concept Chromosome Structures
Concept X Chromosome Inactivation
Concept Chromosomes, Human, Pair 21
Concept Chromosome Painting
Concept Chromosome Mapping
Concept X Chromosome
Academic Article Interview: from Down's syndrome to basic epigenetics and back again.
Academic Article RLIM is dispensable for X-chromosome inactivation in the mouse embryonic epiblast.
Academic Article Regulation of X-linked gene expression during early mouse development by Rlim.
Academic Article SAF-A Requirement in Anchoring XIST RNA to Chromatin Varies in Transformed and Primary Cells.
Academic Article A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains.
Academic Article Inducible XIST-dependent X-chromosome inactivation in human somatic cells is reversible.
Academic Article Rlim-Dependent and -Independent Pathways for X Chromosome Inactivation in Female ESCs.
Academic Article Trisomy silencing by XIST normalizes Down syndrome cell pathogenesis demonstrated for hematopoietic defects in vitro.
Academic Article Silencing Trisomy 21 with XIST in Neural Stem Cells Promotes Neuronal Differentiation.
Academic Article Nascent RNA scaffolds contribute to chromosome territory architecture and counter chromatin compaction.
Academic Article SAF-A mutants disrupt chromatin structure through dominant negative effects on RNAs associated with chromatin.
Search Criteria
  • Chromosomes Human Pair 6