scholarly journals Bat Accelerated Regions Identify a Bat Forelimb Specific Enhancer in the HoxD Locus

2015 ◽  
Author(s):  
Betty M Booker ◽  
Tara Friedrich ◽  
Mandy K Mason ◽  
Julia E VanderMeer ◽  
Jingjing Zhao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Limb Development ◽  
Myotis Lucifugus ◽  
Enhancer Activity ◽  
Mouse Sequence ◽  
Molecular Events ◽  
Mouse Limb ◽  
Morphological Differences ◽  
Drive Gene ◽  
Bat Wing

The molecular events leading to the development of the bat wing remain largely unknown, and are thought to be caused, in part, by changes in gene expression during limb development. These expression changes could be instigated by variations in gene regulatory enhancers. Here, we used a comparative genomics approach to identify regions that evolved rapidly in the bat ancestor but are highly conserved in other vertebrates. We discovered 166 bat accelerated regions (BARs) that overlap H3K27ac and p300 ChIP-seq peaks in developing mouse limbs. Using a mouse enhancer assay, we show that five Myotis lucifugus BARs drive gene expression in the developing mouse limb, with the majority showing differential enhancer activity compared to the mouse orthologous BAR sequences. These include BAR116, which is located telomeric to the HoxD cluster and had robust forelimb expression for the M. lucifugus sequence and no activity for the mouse sequence at embryonic day 12.5. Developing limb expression analysis of Hoxd10-Hoxd13 in Miniopterus natalensis bats showed a high-forelimb weak-hindlimb expression for Hoxd10-Hoxd11, similar to the expression trend observed for M. lucifugus BAR116 in mice, suggesting that it could be involved in the regulation of the bat HoxD complex. Combined, our results highlight novel regulatory regions that could be instrumental for the morphological differences leading to the development of the bat wing.

scholarly journals Deep conservation of wrist and digit enhancers in fish

2014 ◽  
Vol 112 (3) ◽  
pp. 803-808 ◽  
Author(s):  
Andrew R. Gehrke ◽  
Igor Schneider ◽  
Elisa de la Calle-Mustienes ◽  
Juan J. Tena ◽  
Carlos Gomez-Marin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Limb Development ◽  
Expression Patterns ◽  
Late Phase ◽  
Phylogenetic Footprinting ◽  
Molecular Data ◽  
Distal Portion ◽  
Spotted Gar ◽  
Mouse Limb ◽  
And Function

There is no obvious morphological counterpart of the autopod (wrist/ankle and digits) in living fishes. Comparative molecular data may provide insight into understanding both the homology of elements and the evolutionary developmental mechanisms behind the fin to limb transition. In mouse limbs the autopod is built by a “late” phase of Hoxd and Hoxa gene expression, orchestrated by a set of enhancers located at the 5′ end of each cluster. Despite a detailed mechanistic understanding of mouse limb development, interpretation of Hox expression patterns and their regulation in fish has spawned multiple hypotheses as to the origin and function of “autopod” enhancers throughout evolution. Using phylogenetic footprinting, epigenetic profiling, and transgenic reporters, we have identified and functionally characterized hoxD and hoxA enhancers in the genomes of zebrafish and the spotted gar, Lepisosteus oculatus, a fish lacking the whole genome duplication of teleosts. Gar and zebrafish “autopod” enhancers drive expression in the distal portion of developing zebrafish pectoral fins, and respond to the same functional cues as their murine orthologs. Moreover, gar enhancers drive reporter gene expression in both the wrist and digits of mouse embryos in patterns that are nearly indistinguishable from their murine counterparts. These functional genomic data support the hypothesis that the distal radials of bony fish are homologous to the wrist and/or digits of tetrapods.

scholarly journals The Human Accelerated Region HACNS1 modifies developmental gene expression in humanized mice

2019 ◽  
Author(s):  
Emily V. Dutrow ◽  
Deena Emera ◽  
Kristina Yim ◽  
Severin Uebbing ◽  
Acadia A. Kocher ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Evolution ◽  
Limb Development ◽  
Specific Activity ◽  
Limb Bud ◽  
Humanized Mouse ◽  
Enhancer Activity ◽  
Regulatory Pathways ◽  
Embryonic Limb ◽  
Human Specific

AbstractMorphological innovations that arose during human evolution are ultimately encoded in genetic changes that altered development. Human Accelerated Regions (HARs), which include developmental enhancers that harbor a significant excess of human-specific sequence changes, are leading candidates for driving novel physical modifications in humans. Here we examine the role of the HAR HACNS1 (also known as HAR2) in human limb evolution by directly interrogating its cellular and developmental functions in a humanized mouse model. HACNS1 encodes an enhancer with human-specific activity in the developing limb in transgenic mouse reporter assays, and exhibits increased epigenetic signatures of enhancer activity in the human embryonic limb compared to its orthologs in rhesus macaque and mouse. Here we find that HACNS1 maintains its human-specific enhancer activity compared to its chimpanzee ortholog in the mouse embryonic limb, and that it alters expression of the transcription factor gene Gbx2 during limb development. Using single-cell RNA-sequencing, we demonstrate that Gbx2 is upregulated in humanized limb bud chondrogenic mesenchyme, implicating HACNS1-mediated Gbx2 expression in early skeletal patterning. Our findings establish that HARs direct changes in the level and distribution of gene expression during development, and illustrate how humanized mouse models provide insight into regulatory pathways modified in human evolution.

scholarly journals Geminin is required for Hox gene regulation to pattern the developing limb

2020 ◽  
Author(s):  
Emily M.A. Lewis ◽  
Savita Sankar ◽  
Caili Tong ◽  
Ethan Patterson ◽  
Laura E. Waller ◽  
...  
Keyword(s):  
Gene Expression ◽  
Limb Development ◽  
Complex Structure ◽  
Limb Bud ◽  
Conditional Model ◽  
Regulatory Pathways ◽  
Shh Pathway ◽  
Severe Reduction ◽  
Vertebrate Limb ◽  
Mouse Limb

AbstractDevelopment of the complex structure of the vertebrate limb requires carefully orchestrated interactions between multiple regulatory pathways and proteins. Among these, precise regulation of 5’ Hox transcription factor expression is essential for proper limb bud patterning and elaboration of distinct limb skeletal elements. Here, we identified Geminin (Gmnn) as a novel regulator of this process. A conditional model of Gmnn deficiency resulted in loss or severe reduction of forelimb skeletal elements, while both the forelimb autopod and hindlimb were unaffected. 5’ Hox gene expression expanded into more proximal and anterior regions of the embryonic forelimb buds in this Gmnn-deficient model. A second conditional model of Gmnn deficiency instead caused a similar but less severe reduction of hindlimb skeletal elements and hindlimb polydactyly, while not affecting the forelimb. An ectopic posterior SHH signaling center was evident in the anterior hindlimb bud of Gmnn-deficient embryos in this model. This center ectopically expressed Hoxd13, the HOXD13 target Shh, and the SHH target Ptch1, while these mutant hindlimb buds also had reduced levels of the cleaved, repressor form of GLI3, a SHH pathway antagonist. Together, this work delineates a new role for Gmnn in modulating Hox expression to pattern the vertebrate limb.SummaryThis work identifies a new role for Geminin in mouse limb development. Geminin is a nuclear protein that regulates gene expression to control several other aspects of vertebrate development.

scholarly journals Functional mapping of androgen receptor enhancer activity

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Chia-Chi Flora Huang ◽  
Shreyas Lingadahalli ◽  
Tunc Morova ◽  
Dogancan Ozturan ◽  
Eugene Hu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Binding Sites ◽  
Gene Promoters ◽  
Strongly Correlated ◽  
Enhancer Activity ◽  
Drive Gene Expression ◽  
In Vitro Cell Lines ◽  
Drive Gene

Abstract Background Androgen receptor (AR) is critical to the initiation, growth, and progression of prostate cancer. Once activated, the AR binds to cis-regulatory enhancer elements on DNA that drive gene expression. Yet, there are 10–100× more binding sites than differentially expressed genes. It is unclear how or if these excess binding sites impact gene transcription. Results To characterize the regulatory logic of AR-mediated transcription, we generated a locus-specific map of enhancer activity by functionally testing all common clinical AR binding sites with Self-Transcribing Active Regulatory Regions sequencing (STARRseq). Only 7% of AR binding sites displayed androgen-dependent enhancer activity. Instead, the vast majority of AR binding sites were either inactive or constitutively active enhancers. These annotations strongly correlated with enhancer-associated features of both in vitro cell lines and clinical prostate cancer samples. Evaluating the effect of each enhancer class on transcription, we found that AR-regulated enhancers frequently interact with promoters and form central chromosomal loops that are required for transcription. Somatic mutations of these critical AR-regulated enhancers often impact enhancer activity. Conclusions Using a functional map of AR enhancer activity, we demonstrated that AR-regulated enhancers act as a regulatory hub that increases interactions with other AR binding sites and gene promoters.

scholarly journals Heat-induced expression of albumin during early stages of rat embryo development.

1987 ◽  
Vol 7 (12) ◽  
pp. 4599-4602 ◽  
Author(s):  
U K Srinivas ◽  
C J Revathi ◽  
M R Das
Keyword(s):  
Gene Expression ◽  
Heat Shock ◽  
Embryonic Liver ◽  
Rat Embryo ◽  
Adult Liver ◽  
Stages Of Development ◽  
Induced Expression ◽  
Molecular Events ◽  
Internal Change ◽  
Shock Proteins

An examination of heat-induced expression of proteins in tissues from adult and embryonic liver in rats shows that albumin, which is constitutively expressed in adult liver and is not synthesized in embryos before 16 days of gestation, appears in liver cells at earlier stages of development upon heat shock. On the basis of available evidence for the expression of heat shock proteins at distinct stages of development and on the basis of our findings, it may be argued that there could be common molecular events taking place during development and as a result of heat shock. We suggest also that one of the consequences of heat shock could be an internal change of pH within the cell which, in turn, might trigger alterations in gene expression.

scholarly journals Epigenetic events in medulloblastoma development

2005 ◽  
Vol 19 (5) ◽  
pp. 1-13 ◽  
Author(s):  
Janet C. Lindsey ◽  
Jennifer A. Anderton ◽  
Meryl E. Lusher ◽  
Steven C. Clifford
Keyword(s):  
Gene Expression ◽  
Tumor Suppressor Genes ◽  
Molecular Basis ◽  
Gene Disruption ◽  
Functional Role ◽  
Promoter Hypermethylation ◽  
Therapeutic Approaches ◽  
Primary Tumors ◽  
Molecular Events ◽  
Epigenetic Events

Over the last decade, the analysis of genetic defects in primary tumors has been central to the identification of molecular events and biological pathways involved in the pathogenesis of medulloblastoma, the most common malignant brain tumor of childhood. Despite this, understanding of the molecular basis of the majority of cases remains poor. In recent years, the emerging field of epigenetics, which describes heritable alterations in gene expression that occur in the absence of DNA sequence changes, has forced a revision of the understanding of the mechanisms of gene disruption in cancer. Accumulating evidence indicates a significant involvement for epigenetic events in medulloblastoma development. Recent studies have identified a series of candidate tumor suppressor genes (for example, RASSF1A, CASP8, and HIC1) that are each specifically epigenetically inactivated in a large proportion (> 30%) of medulloblastomas by promoter hypermethylation, leading to the silencing of their gene expression. These findings shed new light on medulloblastoma and offer great potential for an improved understanding of its molecular pathology. The authors review the current understanding of epigenetic events in cancer and their contribution to medulloblastoma development. Their nature, origins, and functional role(s) in tumorigenesis are considered, and the authors assess the potential utility of these events as a basis for novel diagnostic and therapeutic approaches.

scholarly journals Gene Expression Profiles at Moxibustioned Site (ST36): A Microarray Analysis

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Hai-Yan Yin ◽  
Yong Tang ◽  
Sheng-Feng Lu ◽  
Ling Luo ◽  
Jia-Ping Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Microarray Analysis ◽  
Expression Profiles ◽  
Alternative Therapy ◽  
Gene Expression Profiles ◽  
Biological Processes ◽  
Physiological Conditions ◽  
Pathological Conditions ◽  
Molecular Events ◽  
Zusanli Acupoint

As a major alternative therapy in Traditional Chinese Medicine, it has been demonstrated that moxibustion could generate a series of molecular events in blood, spleen, and brain, and so forth. However, what would happen at the moxibustioned site remained unclear. To answer this question, we performed a microarray analysis with skin tissue taken from the moxibustioned site also Zusanli acupoint (ST36) where 15-minute moxibustion stimulation was administrated. The results exhibited 145 upregulated and 72 downregulated genes which responded immediately under physiological conditions, and 255 upregulated and 243 downregulated genes under pathological conditions. Interestingly, most of the pathways and biological processes of the differentially expressed genes (DEGs) under pathological conditions get involved in immunity, while those under physiological conditions are involved in metabolism.

Analysis of a tissue-specific enhancer: ARF6 regulates adipogenic gene expression

1992 ◽  
Vol 12 (3) ◽  
pp. 1202-1208
Author(s):  
R A Graves ◽  
P Tontonoz ◽  
B M Spiegelman
Keyword(s):  
Gene Expression ◽  
Cultured Cells ◽  
Mutational Analysis ◽  
Cell Types ◽  
Specific Gene ◽  
Enhancer Activity ◽  
Cis Acting ◽  
Specific Gene Expression ◽  
Nuclear Extracts ◽  
Adipogenic Gene

The molecular basis of adipocyte-specific gene expression is not well understood. We have previously identified a 518-bp enhancer from the adipocyte P2 gene that stimulates adipose-specific gene expression in both cultured cells and transgenic mice. In this analysis of the enhancer, we have defined and characterized a 122-bp DNA fragment that directs differentiation-dependent gene expression in cultured preadipocytes and adipocytes. Several cis-acting elements have been identified and shown by mutational analysis to be important for full enhancer activity. One pair of sequences, ARE2 and ARE4, binds a nuclear factor (ARF2) present in extracts derived from many cell types. Multiple copies of these elements stimulate gene expression from a minimal promoter in preadipocytes, adipocytes, and several other cultured cell lines. A second pair of elements, ARE6 and ARE7, binds a separate factor (ARF6) that is detected only in nuclear extracts derived from adipocytes. The ability of multimers of ARE6 or ARE7 to stimulate promoter activity is strictly adipocyte specific. Mutations in the ARE6 sequence greatly reduce the activity of the 518-bp enhancer. These data demonstrate that several cis- and trans-acting components contribute to the activity of the adipocyte P2 enhancer and suggest that ARF6, a novel differentiation-dependent factor, may be a key regulator of adipogenic gene expression.

Products, genetic linkage and limb patterning activity of a murine hedgehog gene

Development ◽  
1994 ◽  
Vol 120 (11) ◽  
pp. 3339-3353 ◽  
Author(s):  
D.T. Chang ◽  
A. Lopez ◽  
D.P. von Kessler ◽  
C. Chiang ◽  
B.K. Simandl ◽  
...  
Keyword(s):  
Limb Development ◽  
Genetic Linkage ◽  
Pcr Primers ◽  
Amino Acid Identity ◽  
Protein Product ◽  
Proteolytic Processing ◽  
Limb Bud ◽  
Gene Encoding ◽  
Mouse Limb ◽  
Drosophila Embryos

The hedgehog (hh) segmentation gene of Drosophila melanogaster encodes a secreted signaling protein that functions in the patterning of larval and adult structures. Using low stringency hybridization and degenerate PCR primers, we have isolated complete or partial hh-like sequences from a range of invertebrate species including other insects, leech and sea urchin. We have also isolated three mouse and two human DNA fragments encoding distinct hh-like sequences. Our studies have focused upon Hhg-1, a mouse gene encoding a protein with 46% amino acid identity to hh. The Hhg-1 gene, which corresponds to the previously described vhh-1 or sonic class, is expressed in the notochord, ventral neural tube, lung bud, hindgut and posterior margin of the limb bud in developing mouse embryos. By segregation analysis the Hhg-1 gene has been localized to a region in proximal chromosome 5, where two mutations affecting mouse limb development previously have been mapped. In Drosophila embryos, ubiquitous expression of the Hhg-1 gene yields effects upon gene expression and cuticle pattern similar to those observed for the Drosophila hh gene. We also find that cultured quail cells transfected with a Hhg-1 expression construct can induce digit duplications when grafted to anterior or mid-distal but not posterior borders within the developing chick limb; more proximal limb element duplications are induced exclusively by mid-distal grafts. Both in transgenic Drosophila embryos and in transfected quail cells, the Hhg-1 protein product is cleaved to yield two stable fragments from a single larger precursor. The significance of Hhg-1 genetic linkage, patterning activity and proteolytic processing in Drosophila and chick embryos is discussed.

The dominant hemimelia mutation uncouples epithelial-mesenchymal interactions and disrupts anterior mesenchyme formation in mouse hindlimbs

Development ◽  
1999 ◽  
Vol 126 (21) ◽  
pp. 4729-4736
Author(s):  
L. Lettice ◽  
J. Hecksher-Sorensen ◽  
R.E. Hill
Keyword(s):  
Gene Expression ◽  
Pattern Formation ◽  
Limb Development ◽  
Limb Bud ◽  
Mouse Mutation ◽  
Number Of Factors ◽  
Limb Outgrowth ◽  
Gene Functions ◽  
Regulatory Loop ◽  
Limb Initiation

Epithelial-mesenchymal interactions are essential for both limb outgrowth and pattern formation in the limb. Molecules capable of communication between these two tissues are known and include the signaling molecules SHH and FGF4, FGF8 and FGF10. Evidence suggests that the pattern and maintenance of expression of these genes are dependent on a number of factors including regulatory loops between genes expressed in the AER and those in the underlying mesenchyme. We show here that the mouse mutation dominant hemimelia (Dh) alters the pattern of gene expression in the AER such that Fgf4, which is normally expressed in a posterior domain, and Fgf8, which is expressed throughout are expressed in anterior patterns. We show that maintenance of Shh expression in the posterior mesenchyme is not dependent on either expression of Fgf4 or normal levels of Fgf8 in the overlying AER. Conversely, AER expression of Fgf4 is not directly dependent on Shh expression. Also the reciprocal regulatory loop proposed for Fgf8 in the AER and Fgf10 in the underlying mesenchyme is also uncoupled by this mutation. Early during the process of limb initiation, Dh is involved in regulating the width of the limb bud, the mutation resulting in selective loss of anterior mesenchyme. The Dh gene functions in the initial stages of limb development and we suggest that these initial roles are linked to mechanisms that pattern gene expression in the AER.

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