Disrupting the three-dimensional regulatory topology of the Pitx1 locus results in overtly normal development [RESEARCH ARTICLE]

Publication Date:
2018-04-14
Publisher:
The Company of Biologists
Print ISSN:
0950-1991
Electronic ISSN:
1477-9129
Topics:
Biology
Keywords:
Chromatin & epigenetics, Musculoskeletal system
Published by:
http://www.biologists.com/
_version_ 1839208009035677696
autor Sarro, R., Kocher, A. A., Emera, D., Uebbing, S., Dutrow, E. V., Weatherbee, S. D., Nottoli, T., Noonan, J. P.
beschreibung Richard Sarro, Acadia A. Kocher, Deena Emera, Severin Uebbing, Emily V. Dutrow, Scott D. Weatherbee, Timothy Nottoli, and James P. Noonan Developmental gene expression patterns are orchestrated by thousands of distant-acting transcriptional enhancers. However, identifying enhancers essential for the expression of their target genes has proven challenging. Maps of long-range regulatory interactions may provide the means to identify enhancers crucial for developmental gene expression. To investigate this hypothesis, we used circular chromosome conformation capture coupled with interaction maps in the mouse limb to characterize the regulatory topology of Pitx1 , which is essential for hindlimb development. We identified a robust hindlimb-specific interaction between Pitx1 and a putative hindlimb-specific enhancer. To interrogate the role of this interaction in Pitx1 regulation, we used genome editing to delete this enhancer in mouse. Although deletion of the enhancer completely disrupts the interaction, Pitx1 expression in the hindlimb is only mildly affected, without any detectable compensatory interactions between the Pitx1 promoter and potentially redundant enhancers. Pitx1 enhancer null mice did not exhibit any of the characteristic morphological defects of the Pitx1 –/– mutant. Our results suggest that robust, tissue-specific physical interactions at essential developmental genes have limited predictive value for identifying enhancer mutations with strong loss-of-function phenotypes.
citation_standardnr 6234284
datenlieferant ipn_articles
feed_id 1748
feed_publisher The Company of Biologists
feed_publisher_url http://www.biologists.com/
insertion_date 2018-04-14
journaleissn 1477-9129
journalissn 0950-1991
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The Company of Biologists
quelle Development
relation http://dev.biologists.org/cgi/content/short/145/7/dev158550?rss=1
schlagwort Chromatin & epigenetics, Musculoskeletal system
search_space articles
shingle_author_1 Sarro, R., Kocher, A. A., Emera, D., Uebbing, S., Dutrow, E. V., Weatherbee, S. D., Nottoli, T., Noonan, J. P.
shingle_author_2 Sarro, R., Kocher, A. A., Emera, D., Uebbing, S., Dutrow, E. V., Weatherbee, S. D., Nottoli, T., Noonan, J. P.
shingle_author_3 Sarro, R., Kocher, A. A., Emera, D., Uebbing, S., Dutrow, E. V., Weatherbee, S. D., Nottoli, T., Noonan, J. P.
shingle_author_4 Sarro, R., Kocher, A. A., Emera, D., Uebbing, S., Dutrow, E. V., Weatherbee, S. D., Nottoli, T., Noonan, J. P.
shingle_catch_all_1 Disrupting the three-dimensional regulatory topology of the Pitx1 locus results in overtly normal development [RESEARCH ARTICLE]
Chromatin & epigenetics, Musculoskeletal system
Richard Sarro, Acadia A. Kocher, Deena Emera, Severin Uebbing, Emily V. Dutrow, Scott D. Weatherbee, Timothy Nottoli, and James P. Noonan Developmental gene expression patterns are orchestrated by thousands of distant-acting transcriptional enhancers. However, identifying enhancers essential for the expression of their target genes has proven challenging. Maps of long-range regulatory interactions may provide the means to identify enhancers crucial for developmental gene expression. To investigate this hypothesis, we used circular chromosome conformation capture coupled with interaction maps in the mouse limb to characterize the regulatory topology of Pitx1 , which is essential for hindlimb development. We identified a robust hindlimb-specific interaction between Pitx1 and a putative hindlimb-specific enhancer. To interrogate the role of this interaction in Pitx1 regulation, we used genome editing to delete this enhancer in mouse. Although deletion of the enhancer completely disrupts the interaction, Pitx1 expression in the hindlimb is only mildly affected, without any detectable compensatory interactions between the Pitx1 promoter and potentially redundant enhancers. Pitx1 enhancer null mice did not exhibit any of the characteristic morphological defects of the Pitx1 –/– mutant. Our results suggest that robust, tissue-specific physical interactions at essential developmental genes have limited predictive value for identifying enhancer mutations with strong loss-of-function phenotypes.
Sarro, R., Kocher, A. A., Emera, D., Uebbing, S., Dutrow, E. V., Weatherbee, S. D., Nottoli, T., Noonan, J. P.
The Company of Biologists
0950-1991
09501991
1477-9129
14779129
shingle_catch_all_2 Disrupting the three-dimensional regulatory topology of the Pitx1 locus results in overtly normal development [RESEARCH ARTICLE]
Chromatin & epigenetics, Musculoskeletal system
Richard Sarro, Acadia A. Kocher, Deena Emera, Severin Uebbing, Emily V. Dutrow, Scott D. Weatherbee, Timothy Nottoli, and James P. Noonan Developmental gene expression patterns are orchestrated by thousands of distant-acting transcriptional enhancers. However, identifying enhancers essential for the expression of their target genes has proven challenging. Maps of long-range regulatory interactions may provide the means to identify enhancers crucial for developmental gene expression. To investigate this hypothesis, we used circular chromosome conformation capture coupled with interaction maps in the mouse limb to characterize the regulatory topology of Pitx1 , which is essential for hindlimb development. We identified a robust hindlimb-specific interaction between Pitx1 and a putative hindlimb-specific enhancer. To interrogate the role of this interaction in Pitx1 regulation, we used genome editing to delete this enhancer in mouse. Although deletion of the enhancer completely disrupts the interaction, Pitx1 expression in the hindlimb is only mildly affected, without any detectable compensatory interactions between the Pitx1 promoter and potentially redundant enhancers. Pitx1 enhancer null mice did not exhibit any of the characteristic morphological defects of the Pitx1 –/– mutant. Our results suggest that robust, tissue-specific physical interactions at essential developmental genes have limited predictive value for identifying enhancer mutations with strong loss-of-function phenotypes.
Sarro, R., Kocher, A. A., Emera, D., Uebbing, S., Dutrow, E. V., Weatherbee, S. D., Nottoli, T., Noonan, J. P.
The Company of Biologists
0950-1991
09501991
1477-9129
14779129
shingle_catch_all_3 Disrupting the three-dimensional regulatory topology of the Pitx1 locus results in overtly normal development [RESEARCH ARTICLE]
Chromatin & epigenetics, Musculoskeletal system
Richard Sarro, Acadia A. Kocher, Deena Emera, Severin Uebbing, Emily V. Dutrow, Scott D. Weatherbee, Timothy Nottoli, and James P. Noonan Developmental gene expression patterns are orchestrated by thousands of distant-acting transcriptional enhancers. However, identifying enhancers essential for the expression of their target genes has proven challenging. Maps of long-range regulatory interactions may provide the means to identify enhancers crucial for developmental gene expression. To investigate this hypothesis, we used circular chromosome conformation capture coupled with interaction maps in the mouse limb to characterize the regulatory topology of Pitx1 , which is essential for hindlimb development. We identified a robust hindlimb-specific interaction between Pitx1 and a putative hindlimb-specific enhancer. To interrogate the role of this interaction in Pitx1 regulation, we used genome editing to delete this enhancer in mouse. Although deletion of the enhancer completely disrupts the interaction, Pitx1 expression in the hindlimb is only mildly affected, without any detectable compensatory interactions between the Pitx1 promoter and potentially redundant enhancers. Pitx1 enhancer null mice did not exhibit any of the characteristic morphological defects of the Pitx1 –/– mutant. Our results suggest that robust, tissue-specific physical interactions at essential developmental genes have limited predictive value for identifying enhancer mutations with strong loss-of-function phenotypes.
Sarro, R., Kocher, A. A., Emera, D., Uebbing, S., Dutrow, E. V., Weatherbee, S. D., Nottoli, T., Noonan, J. P.
The Company of Biologists
0950-1991
09501991
1477-9129
14779129
shingle_catch_all_4 Disrupting the three-dimensional regulatory topology of the Pitx1 locus results in overtly normal development [RESEARCH ARTICLE]
Chromatin & epigenetics, Musculoskeletal system
Richard Sarro, Acadia A. Kocher, Deena Emera, Severin Uebbing, Emily V. Dutrow, Scott D. Weatherbee, Timothy Nottoli, and James P. Noonan Developmental gene expression patterns are orchestrated by thousands of distant-acting transcriptional enhancers. However, identifying enhancers essential for the expression of their target genes has proven challenging. Maps of long-range regulatory interactions may provide the means to identify enhancers crucial for developmental gene expression. To investigate this hypothesis, we used circular chromosome conformation capture coupled with interaction maps in the mouse limb to characterize the regulatory topology of Pitx1 , which is essential for hindlimb development. We identified a robust hindlimb-specific interaction between Pitx1 and a putative hindlimb-specific enhancer. To interrogate the role of this interaction in Pitx1 regulation, we used genome editing to delete this enhancer in mouse. Although deletion of the enhancer completely disrupts the interaction, Pitx1 expression in the hindlimb is only mildly affected, without any detectable compensatory interactions between the Pitx1 promoter and potentially redundant enhancers. Pitx1 enhancer null mice did not exhibit any of the characteristic morphological defects of the Pitx1 –/– mutant. Our results suggest that robust, tissue-specific physical interactions at essential developmental genes have limited predictive value for identifying enhancer mutations with strong loss-of-function phenotypes.
Sarro, R., Kocher, A. A., Emera, D., Uebbing, S., Dutrow, E. V., Weatherbee, S. D., Nottoli, T., Noonan, J. P.
The Company of Biologists
0950-1991
09501991
1477-9129
14779129
shingle_title_1 Disrupting the three-dimensional regulatory topology of the Pitx1 locus results in overtly normal development [RESEARCH ARTICLE]
shingle_title_2 Disrupting the three-dimensional regulatory topology of the Pitx1 locus results in overtly normal development [RESEARCH ARTICLE]
shingle_title_3 Disrupting the three-dimensional regulatory topology of the Pitx1 locus results in overtly normal development [RESEARCH ARTICLE]
shingle_title_4 Disrupting the three-dimensional regulatory topology of the Pitx1 locus results in overtly normal development [RESEARCH ARTICLE]
timestamp 2025-07-31T23:44:00.355Z
titel Disrupting the three-dimensional regulatory topology of the Pitx1 locus results in overtly normal development [RESEARCH ARTICLE]
titel_suche Disrupting the three-dimensional regulatory topology of the Pitx1 locus results in overtly normal development [RESEARCH ARTICLE]
topic W
uid ipn_articles_6234284