Search

X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of ‘escape’ from inactivation varying between genes and individuals. The extent to which XCI is shared between cells and tissues remains poorly characterized, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression and phenotypic traits. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.

The realization that nuclear distribution of DNA, RNA, and proteins differs between cell types and developmental stages suggests that nuclear organization serves regulatory functions. Understanding the logic of nuclear architecture and how it contributes to differentiation and cell fate commitment remains challenging. Here, we use soft X-ray tomography (SXT) to image chromatin organization, distribution, and biophysical properties during neurogenesis in vivo. Our analyses reveal that chromatin with similar biophysical properties forms an elaborate connected network throughout the entire nucleus. Although this interconnectivity is present in every developmental stage, differentiation proceeds with concomitant increase in chromatin compaction and re-distribution of condensed chromatin toward the nuclear core. HP1β, but not nucleosome spacing or phasing, regulates chromatin rearrangements because it governs both the compaction of chromatin and its interactions with the nuclear envelope. Our experiments introduce SXT as a powerful imaging technology for nuclear architecture.

BACKGROUND: Human herpesvirus 8 (HHV-8) has been detected in Kaposi sarcoma (KS) and other lesions in patients both seropositive and seronegative for the human immunodeficiency virus (HIV). Kaposi sarcoma has been reported to develop in a disproportionate number of patients with pemphigus. Since HHV-8 is so strongly associated with KS, we wondered whether HHV-8 is present in pemphigus lesions from patients without KS or HIV infection. Pemphigus lesions and skin from healthy individuals were coded in a blinded fashion. Tissue-extracted DNA was tested using polymerase chain reaction, Southern blot hybridization, and automated sequencing of the polymerase chain reaction products for the presence of HHV-8 DNA. Six patients had pemphigus foliaceus, 6 had pemphigus vulgaris, and 2 had KS; 10 healthy individuals were used as controls. All 24 patients were HIV seronegative. OBSERVATION: Lesional skin from 4 of the 6 patients with pemphigus vulgaris, all 6 of the patients with pemphigus foliaceus, and both positive controls (KS) tested positive for HHV-8 DNA. Furthermore, the HHV-8 DNA sequences for KS330233 differed between all 6 DNA specimens from pemphigus foliaceus, while 3 of the 4 DNA specimens from pemphigus vulgaris were identical. However, HHV-8 DNA was absent in all normal human skin analyzed. CONCLUSIONS: This report expands the spectrum of lesions found to contain HHV-8 DNA sequences and suggests that HHV-8 might have trophism for pemphigus lesions.Arch Dermatol. 1997;133:1247-1251

Data from 384 individuals participating in a worksite skin cancer screening program were used to assess racial/ethnic differences in attitudes toward and practice of prevention and early detection of skin cancer. Caucasians and Hispanics were more likely than African Americans to report having used a sunscreen during the past year. Caucasians performed skin self-examination more frequently than Hispanics, but African Americans did not differ in their frequency of skin self-examination from the other two groups. African Americans and Hispanics reported that they would be less likely than Caucasians to seek immediate follow-up care for suspicious skin lesions. Both similarities and differences were found in a variety of health belief variables across the three groups. These findings suggest a need for intensified efforts at primary and secondary prevention of skin cancer among African Americans.

Mucoepidermoid carcinomas are malignant neoplasms that rarely involve the skin. Composed of both mucus-secreting cells and epidermoid-type cells in various proportions, mucoepidermoid carcinomas occur most commonly in salivary glands. In this case report, we describe a high-grade mucoepidermoid carcinoma with cutaneous involvement. Although this patient was referred for Mohs’ micrographic surgery, further evaluation showed either direct or metastatic extension from the parotid gland to skin and distant metastases to the lung and bone. Despite extensive bone involvement, serum levels of ionized calcium, phosphorus, and lactate dehydrogenase remained normal. In view of the widespread metastases, the treatment plan was altered to radiotherapy and chemotherapy instead of surgery. Instructive lessons from this case include the recognition by dermatologists of this rare entity, the importance of a detailed history and complete evaluation of the patient before determining appropriate therapy, and the necessity of individualizing diagnostic tests to a particular patient. (J Am Acad Dermatol 1997;37:340-2.)

Predesquamin is a glycoprotein that we have isolated from human epidermis. Its monospecific polyclonal antibody immunolocalizes to the lower stratum corneum. We have previously found that it is not expressed ordinarily in primary keratinocyte cultures, but that it is expressed in a serum-containing medium that is supplemented with interferon-γ. Under these conditions, we observed larger outer squames and a more mature pattern of desquamation. We now demonstrate, by adding predesquamin directly to the culture medium without the cytokine, that the morphological changes are caused by predesquamin (and the role of IFN-γ in the previous experiment was to stimulate the expression of predesquamin).

First described by Shelley and Wood in 1977, mid-dermal elastolysis (MDE) is a rare acquired disorder in which there is a bandlike absence of elastic tissue limited to the mid-dermis. In their patient, MDE developed in an area previously involved with recurrent episodes of urticaria. We describe a 15-year-old white girl with well-circumscribed, minimally palpable yellow-white plaques and wrinkling diagnosed histologically as MDE in areas clincally diagnosed 5 years previously as granuloma annulare. As in the first described patient, five years elapsed between clearance of the original skin lesions and the clinical appearance of MDE. To our knowldege, we report the first adolescent case of MDE localized to previous sites of lesions clinically consistent with granuloma annulare and propose that MDE represents an abnormal end-stage reaction to multiple processes. (J Am Acad Dermatol 1997;37:870-2.)

This corrects the article DOI: 10.1038/nature24265

Persistent expression of fetal hemoglobin (HbF) beyond the neonatal period is a rare, naturally-occurring condition, referred to as the Hereditary Persistence of Fetal Hemoglobin, which substantially ameliorates the pathology of Sickle Cell Disease (SCD) and β-thalassemia (β-thal). Extensive human genetic and epidemiologic studies have demonstrated that this condition is associated with one of several specific point mutations or deletions that lead to expression of γ-globin, resulting in upregulation of HbF. Our strategy is to use the CRISPR/Cas9 genome editing technology in human primary CD34+ hematopoietic stem and progenitor cells (HSPCs) to efficiently re-create specific genetic variants associated with elevated HbF and to evaluate their safety, effectiveness and durability as a potential therapeutic strategy to treat SCD and β-thal.

The occurrence of Langerhans cell histiocytosis (LCH) and malignancy in the same patient is rare. When LCH occurs concomitantly with acute leukemia, distinct temporal patterns often exist; acute myelogenous leukemia (AML) typically succeeds LCH, whereas acute lymphocytic leukemia (ALL) usually precedes it. We report a case of LCH developing in a child while in remission for ALL. Unique features of this case include the disseminated nature of the LCH and the death of the patient from LCH rather than ALL. (J Am Acad Dermatol 2001;45:S233-4.)

Tuberculosis poses a serious diagnostic and therapeutic problem, even in developed countries. As originally described,1 tuberculids are cutaneous eruptions that result from an abnormally marked host response to the presence of mycobacteria. One such tuberculid is erythema induratum of Bazin (EIB), in which Mycobacterium tuberculosis has recently been detected.2 PATIENTS AND METHODS. Sixteen formaldehyde solution— fixed, paraffin-embedded blocks of EIB were collected from 1988 to 1995 (Table).3 As a positive control in all procedures, a paraffin-embedded sample of M tuberculosis as confirmed by mycobacterial culture was included. As a negative control, an acrochordon specimen was included. Reagent controls were also included.DNA was extracted from paraffin-embedded blocks as previously described4 and analyzed for M tuberculosis DNA by polymerase chain reaction (PCR) using a primer specific for M tuberculosis and M bovis.5 The methods outlined by Eisenach et al5 were adhered to stringently with 1

REPORT OF A CASE A 40-year-old white woman presented in October 1993 with an increase in number of painful new lesions on her left arm. These lesions, which first appeared in May 1991, throbbed more severely after a bath or shower. The patient denied any family history of a similar condition. Her medical history was otherwise unremarkable except for psoriasis, which was responsive to treatment with topical steroids.Physical examination revealed multiple, firm, tender blue nodules, 3 to 4 mm in diameter, on the left side of the patient's face and trunk and on her left arm and leg (Figure 1). Simple excision of individual lesions provided symptomatic relief without recurrence. However, new lesions have continued to develop in the same areas in which the original lesions occurred.A biopsy specimen obtained from a lesion on the left arm was stained with hematoxylin-eosin (Figure 2).What is your diagnosis? DIAGNOSIS: Multiple glomus tumors (glomangiomas).

REPORT OF A CASE A 42-year-old white woman underwent bilateral leg sclerotherapy with hypertonic saline in May 1988. Subsequent to this, multiple 1- to 2-cm, tender, erythematous, firm subcutaneous nodules developed on both legs. A punch biopsy specimen was interpreted as erythema nodosum. An extensive workup for collagen vascular and infectious diseases was negative. She received trials of tetracycline, prednisone, and potassium iodide, with a limited response to prednisone only.In February 1989, dermatitis herpetiformis developed. This diagnosis was confirmed by skin biopsy and direct immunofluorescence. This problem remains under control with dapsone (150 mg/d orally).Physical examination revealed multiple 1to 2-cm erythematous tender nodules on both legs (Figure 1). The nodules were more prevalent on the anterior aspect of the legs with some on the posterior aspect of the legs and thighs. No regional adenopathy was present, and the remainder of the physical examination showed normal findings except

We read with interest the article by Arbiser et al in the June 1994 issue of the Archives.1 They described two patients with erythrodermic psoriasis in whom rapid improvement was seen after initiation of occlusive therapy with topical class 1 steroids. Because of potential side effects from widespread use of class 1 steroids under occlusion and the expense of such treatment, we have reservations about the use of very potent steroids under occlusion as initial therapy.In both cases reported, a coexisting infection existed that was not treated with antibiotics until the patient was hospitalized. Reported precipitating factors of erythrodermic psoriasis include preceding or coexisting infections, and an untreated coexisting infection can prevent response to treatment. In our experience, occlusive therapy with a mixture of eucerin and 0.1% triamcinolone cream for 15 to 20 minutes two to three times a day produces clearance of erythrodermic psoriasis in 3 days,